4. The Cells of The Nervous System

Question 1

Neurons and Glia share many characteristics with cells in general. However, neurons are specially endowed with the ability to communicate precisely and rapidly with other cells at distant sites in the body. What two features give neurons this ability?

Answer 1

First, they have a high degree of morphological and functional asymmetry: Neurons have receptive dendrites at one end and a transmitting axon at the other. This arrangement is the structural basis for unidirectional neuronal signalling.

Second, neurons are both electrically and chemically excitable. The cell membrane of neurons contains specialised proteins—ion channels and receptors—that facilitate the flow of specific inorganic ions, thereby redistributing charge and creating electrical currents that alter the voltage across the membrane. These changes in charge can produce a wave of depolarisation in the form of action potentials along the axon, the usual way a signal travels within the neuron.

Question 2

Are Glia also excitable in this manner?

Answer 2

Glia are less excitable, but their membranes contain transporter proteins that facilitate the uptake of ions as well as proteins that remove neurotransmitter molecules from the extracellular space, thus regulating neuronal function.

Question 3

What determines what molecules the neurons make?

Answer 3

Although neurons all inherit the same complement of genes, each expresses a restricted set and thus produces only certain molecules—enzymes, structural proteins, membrane constituents, and secretory products—and not others. In large part this expression depends on the cell’s developmental history. In essence each cell is the set of molecules that it makes.

Question 4

Where do (1) neurons and (2) glia develop?

Answer 4

Neurons and glia develop from common neuroepithelial cells of the embryonic nervous system and thus share many structural and molecular characteristics.

Question 5

What are the boundaries of these cells defined by? How does this compare to other biological cells?

Answer 5

The boundaries of these cells are defined by the cell membrane or plasmalemma, which has the asymmetric bilayer structure of all biological membranes and provides a hydrophobic barrier impermeable to most water-soluble substances.

Question 6

What two main components compose cytosoplasm?

Answer 6

Cytoplasm has two main components: cytosol and membranous organelles.

Question 7

What is cytosol?

Answer 7

Cytosol is the aqueous phase of cytoplasm. In this phase only a few proteins are actually free in solution. With the exception of some enzymes that catalyse metabolic reactions, most proteins are organised into functional complexes.

Question 8

What do these ‘functional complexes’ of proteins consist of?

Answer 8

A recent subdiscipline called proteomics has determined that these complexes can consist of many distinct proteins, none of which are covalently linked to another.

For example, the cytoplasmic tail of the N-methyl-d-aspartate (NMDA)-type glutamate receptor, a membrane-associated protein that mediates excitatory synaptic transmission in the central nervous system, is anchored in a large complex of more than 100 scaffold proteins and protein-modifying enzymes.

Question 9

What are meant by scaffold proteins? **

Answer 9

They are essential regulators of many important signalling pathways.

Question 10

What are the four major functions of scaffold proteins? **

Answer 10

1. Tether signalling components to increase their efficiency (e.g holding signalling components to target proteins)
2. They localise signalling components to their specific regions e.g a nucleus, mitochondrian etc
3. Coordinate/ regulate positive (excitatory) or negative (inhibitory) feedback functions
4. Insulates components from inactivation or degradation (e.g by keeping them apart from enzymes which de-activate them)

Question 11

Name and describe two organelles in the cytosol and their respective functions

Answer 11

Ribosomes, the organelle on which messenger RNA (mRNA) molecules are translated, are made up of several protein subunits.

Proteasomes, large multi-enzyme organelles that degrade ubiquitinated proteins (a process described later), are also present throughout the cytosol of neurons and glia.

Question 12

What is included in membranus organelles?

Answer 12

Membranous organelles, the second main compo- nent of cytoplasm, include mitochondria and peroxisomes as well as a complex system of tubules, vesicles, and cisternae called the vacuolar apparatus.

Question 13

What functions do mitochondria and peroxisomes carry out?

Answer 13

Mitochondria and peroxisomes process molecular oxygen.

Question 14

What is the difference in the functions of mitochondia and peroxisomes?

Answer 14

Mitochondria generate adenosine triphosphate (ATP), the major molecule by which cellular energy is transferred or spent, whereas peroxisomes prevent accumulation of the strong oxidising agent hydrogen peroxide.

Question 15

Are these organelles functionally continuous with the vacuolar apparatus? Why or why not?

Answer 15

Thought to be derived from symbiotic organisms that invaded eukaryotic cells early in evolution, these two organelles are not functionally continuous with the vacuolar apparatus.

Question 16

What is included in the vacuolar apparatus?

Answer 16

The vacuolar apparatus includes the rough endoplasmic reticulum, the smooth endoplasmic reticulum, the Golgi complex, secretory vesicles, endosomes, lysosomes, and a multiplicity of transport vesicles that interconnect these various compartments (see docs)

Question 17

What is meant by the term lumen? **

Answer 17

In biology, a lumen is the inside space of a tubular structure, such as an artery or intestine.

Question 18

What does the lumen of the vacuolar apparatus correspond to?

Answer 18

Their lumen corresponds topologically to the outside of the cell; consequently, the inner leaflet of their lipid bilayer corresponds to the outer leaflet of the plasmalemma.

Question 19

What is meant by the endoplasmic reticulum?

Answer 19

A network of membranous tubules within the cytoplasm of a eukaryotic cell, continuous with the nuclear membrane. It usually has ribosomes attached and is involved in protein and lipid synthesis.

Question 20

The major subcompartments of this system are anatomically discontinuous, but they remain functionally connected. How is this possible? Give an example

Answer 20

Membranous and lumenal material is moved from one compartment to another by means of transport vesicles. For example, proteins and phospholipids synthesised in the rough endoplasmic reticulum (the portion of the reticulum nearest the nucleus and studded with ribosomes) and the smooth endoplasmic reticulum are transported to the Golgi complex and then to secretory vesicles, which empty their contents when the vesicle membrane fuses with the plasmalemma (a process called exocytosis). This secretory pathway serves to add membranous components to the plasmalemma and also to discharge any contents of the secretory vesicles into the extracellular space.

Question 21

Whats the difference of mRNA entering a free ribosome or a ribosome in the E.R in a normal cell? **

Answer 21

Free ribosomes typically code for proteins to be used inside the cell, while the proteins generated by ribosomes on the E.R can be transported for use outside the cell as described previously via a vesicle constructed of the ER membrane to the golgi apparatus where it goes through a maturation process so that the fully manufactured protein, ready to be used, then can be transported outside the cell or in the membrane itself

Question 22

Conversely, how is plasmalemmal membrane taken into the cell?

Answer 22

Conversely, plasmalemmal membrane is taken into the cell in the form of endocytic vesicles (endocytosis). These are incorporated into early endosomes, sorting compartments that are concentrated at the cell’s periphery. The incorporated membrane, which typically contains specific proteins such as receptors, is then either shuttled back to the plasmalemma by vesicles for recycling or directed to late endosomes and eventually to mature lysosomes for degradation.

Question 23

In what regard does the smooth endoplasmic reticulum act as a store?

Answer 23

The smooth endoplasmic reticulum also acts as a regulated internal Ca2+ store throughout the neuronal cytoplasm

Question 24

What is meant by the nuclear envelope?

Answer 24

A specialised portion of the rough endoplasmic reticulum forms the nuclear envelope, a spherical flattened cisterna that surrounds chromosomal DNA and its associated proteins (histones, transcription factors, polymerases, and isomerases ) and defines the nucleus

Question 25

What are histones, polymerases, and isomerases mentioned previously? **

Answer 25

A histone is a protein that provides structural support for a chromosome. Each chromosome contains a long molecule of DNA, which must fit into the cell nucleus. To do that, the DNA wraps around complexes of histone proteins, giving the chromosome a more compact shape.

Isomerases: general class of enzymes that convert a molecule from one isomer to another

polymerases: enzymes that catalyse the synthesis of DNA or RNA polymers whose sequence is complementary to the original template

Question 26

Why is it presumed that the nuclear envelope evolved?

Answer 26

Because the nuclear envelope is continuous with other portions of the endoplasmic reticulum and to the other membranes of the vacuolar apparatus, it is presumed to have evolved as an invagination (being turned inside out or folded back on itself to form a cavity or pouch) of the plasmalemma to ensheathe eukaryotic chromosomes.

Question 27

What are the purpose of nuclear pores in the nuclear envelope?

Answer 27

The nuclear envelope is interrupted by nuclear pores, where fusion of the inner and outer membranes of the envelope results in the formation of hydrophilic channels through which proteins and RNA are exchanged between the cytoplasm proper and the nuclear cytoplasm.

Question 28

Even though nucleoplasm and cytoplasm are continuous domains of cytosol, what is required for molecules to pass through the nuclear pores?

Answer 28

Only molecules with molecular weights less than 5,000 can pass through the nuclear pores freely by diffusion. Larger molecules need help. Some proteins have special nuclear localisation signals, domains that are composed of a sequence of basic amino acids (arginine and lysine) that are recognised by soluble proteins called nuclear import receptors (importins). At a nuclear pore this complex is guided into the nucleus by another group of proteins called nucleoporins.

Question 29

To what extent are the organelles found in the cytoplasm of the cell body found in the dendrites of the cell?

Answer 29

The cytoplasm of the nerve cell body extends into the dendritic tree without functional differentiation. Generally, all organelles in the cytoplasm of the cell body are also present in dendrites, although the densities of the rough endoplasmic reticulum, Golgi complex, and lysosomes rapidly diminish with distance from the cell body.

Question 30

Where is the smooth endoplasmic reticulum prominent in the dendrites?

Answer 30

In dendrites the smooth endoplasmic reticulum is prominent at the base of thin processes called spines, the receptive portion of excitatory synapses.

Question 31

What are presumed to serve as local protein synthesis in the dendrites?

Answer 31

Concentrations of polyribosomes in dendritic spines are presumed to serve local protein synthesis

Question 32

To what extent are the organelles found in the cytoplasm of the cell body found in the axon and axon hillock of the cell?

Answer 32

In contrast to the continuity of the cell body and dendrites, a sharp functional boundary exists between the cell body at the axon hillock, where the axon emerges. Ribosomes, rough endoplasmic reticulum, and the Golgi complex—the organelles that com- prise the main biosynthetic machinery for proteins in the neuron—are generally excluded from axons. Lysosomes and certain proteins are also excluded.

Question 33

If these organelles are excluded from the axons of neurons, what are these axons ‘rich’ in?

Answer 33

Axons are rich in synaptic vesicles and their precursor membranes.

Question 34

What roles does the cytoskeleton carry out?

Answer 34

The cytoskeleton determines the shape of a cell and is responsible for the asymmetric distribution of organelles within the cytoplasm.

Question 35

What is the cytoskeleton composed of?

Answer 35

It includes three filamentous (thread-like) structures: microtubules, neurofilaments, and microfilaments. These filaments and associated proteins account for approximately a quarter of the total protein in the cell.

Question 36

Describe micro-tubules as they appear in the cytoskeleton

Answer 36

Microtubules form long scaffolds that extend from one end of a neuron to the other and play a key role in developing and maintaining cell shape. A single microtubule can be as long as 0.1 mm

Question 37

What are microtubules composed of?

Answer 37

Microtubules are constructed of protofilaments, each of which consists of multiple pairs of α- and β-tubulin subunits arranged longitudinally along the microtubule. Each protofilament is made up of a column of alternating α- and β-tubulin subunits . Tubulin subunits bind to neighbouring subunits along the protofilament and also laterally between adjacent protofilaments.

Question 38

Comment on the tubulin dimer and how it affects the structure of the microtubule

Answer 38

The tubulin dimer (compound formed of one of each of α- and β-tubulin) has a polar structure: The negative end is oriented to the centre of the cell while the positive end extends out to the periphery, to the dendrites and axon.

Question 39

How do microtubules grow in size? What happens when they stop growing?

Answer 39

Microtubules grow by addition of guanosine triphosphate (GTP)-bound tubulin dimers at their positive end, the end that points to the periphery. Shortly after polymerisation the GTP is hydrolysed to guanosine diphosphate (GDP). When a microtubule stops growing, its positive end is capped by a GDP-bound tubulin monomer.

Question 40

Comment on the affinity for the GDP-bound tubulin for the polymer and how this impacts, or could impact, the microtubule

Answer 40

Given the low affinity of the GDP-bound tubulin for the polymer, this would lead to catastrophic depolymerisation unless the microtubules were stabilised by interaction with other proteins.

Question 41

When are microtubules more stable and when are they not? Why is this?

Answer 41

While microtubules undergo rapid cycles of polymerisation and depolymerisation in dividing cells, in mature dendrites and axons they are much more stable. This stability is caused by microtubule-associated proteins (MAPs) that promote the oriented polymerisation and assembly of the tubulin polymers.

Question 42

How do MAPs in axons compare to those in dendrites?

Answer 42

MAPs in axons differ from those in dendrites. For example, MAP2 is present in dendrites but not in axons, whereas tau and MAP3 are present.

Question 43

What diseases are tau proteins associated with and how?

Answer 43

In Alzheimer disease and some other degenerative disorders tau proteins are modified and abnormally polymerised, forming a characteristic lesion called the neurofibrillary tangle

Question 44

Comment on Tubulin’s genetic encoding

Answer 44

Tubulins are encoded by a multigene family. At least six genes code the α- and β-subunits. Because of the expression of the different genes or post transcriptional modifications more than 20 isoforms of tubulin are present in the brain.

Question 45

Describe neurofilaments in regards to their function and frequency

Answer 45

Neurofilaments, 10 nm in diameter, are the bones of the cytoskeleton. They are the most abundant fibrillar component in axons; on average there are 3 to 10 times more neurofilaments than microtubules in an axon.

Question 46

Describe the composition and structure of neurofilaments

Answer 46

Neurofilaments are built with fibers that twist around each other to produce coils of increasing thickness. The thinnest units are monomers that form coiled-coil heterodimers. These dimers form a tetrameric complex that becomes the protofilament. Two protofilaments become a protofibril, and three protofibrils are helically twisted to form the 10 nm diameter neurofilament. (see docs)

Question 47

Comment on the stability of neurofilaments

Answer 47

Unlike microtubules, neurofilaments are stable and almost totally polymerized in the cell.

Question 48

Describe microfilaments in regards to their structure, function and composition.

Answer 48

At 3–7 nm in diameter microfilaments are the thinnest of the three main types of fibers that make up the cytoskeleton. Like thin filaments of muscle, microfilaments are made up of two strands of polymerized globular actin monomers, each bearing an ATP or adenosine diphosphate (ADP), wound into a double-stranded helix.

Question 49

What is Actin?

Answer 49

Actin is a major constituent of all cells, perhaps the most abundant animal protein in nature. There are several closely related molecular forms: the α actin of skeletal muscle and at least two other molecular forms, β and γ. Each is encoded by a different gene.

Question 50

What form of Actin is found in neurons of higher vertebrates?

Answer 50

Neural actin in higher vertebrates is a mixture of the β and γ species, which differ from muscle actin by a few amino acid residues.

Question 51

To what extent is Actin generalisable across 1) different cell types 2) species?

Answer 51

Most actin molecules are highly conserved (haven’t changed much), not only in different cell types of a species but also in organisms as distantly related as humans and protozoa.

Question 52

Comment on the length and location of microfilaments

Answer 52

Unlike microtubules and neurofilaments, actin filaments are short. They are concentrated at the cell’s periphery in the cortical cytoplasm just underneath the plasmalemma, where they form a dense network with many actin-binding proteins (eg, spectrin-fodrin, ankyrin, talin, and actinin).

Question 53

What role does this matrix (the dense network with many actin-binding proteins along periphery of cytoplasm) carry out?

Answer 53

This matrix plays a key role in the dynamic function of the cell’s periphery, such as the motility of growth cones (the growing tips of axons) during development, generation of specialised microdomains at the cell surface, and the formation of pre- and postsynaptic morphological specialisations.

Question 54

Comment on the stability of microfilaments

Answer 54

Like microtubules, microfilaments undergo cycles of polymerisation and depolymerisation. At any one time approximately half the total actin in a cell can exist as unpolymerised monomers.

Question 55

What is the state of actin ‘controlled’ by?

Answer 55

The state of actin is controlled by binding proteins, which facilitate assembly and limit polymer length by capping the rapidly growing end of the filament or by severing it. Other binding proteins crosslink or bundle microfilaments.

Question 56

What does this dynamic state of microtubules and microfilaments allow for?

Answer 56

The dynamic state of microtubules and microfilaments permits a mature neuron to retract old axons and dendrites and extend new ones. This structural plasticity is thought to be a major factor in changes of synaptic connections and efficacy, and therefore cellular mechanisms of long-term memory and learning.

Question 57

Why are the neurofibrillary tangles problematic in Alzheimer’s patients?

Answer 57

In normal neurons tau is either bound to micro- tubules or free in the cytosol. In the tangles it is not bound to microtubules but is highly insoluble. The accumulations disturb the polymerisation of tubulin and therefore interfere with axonal transport. Consequently, the shape of the neuron is not maintained.

Question 58

Are tau accumulations exclusive to alzheimer’s patients?

Answer 58

No, Tau accumulations are also found in neurons of patients with progressive supranuclear palsy, a movement disorder, and in patients with frontotemporal dementias, a group of neurodegenerative disorders that affect the frontal and temporal lobes. The familial forms of fronto temporal dementias are caused by mutations in the tau gene.

Question 59

Give two other examples, apart from tau proteins in Alzheimers patients, of abnormal accumulations of proteins being hallmarks of many neurological disorders (Hint: Thesis!)

Answer 59

Extracellular deposits of polymerized β-amyloid peptides
in Alzheimer disease create an amyloid plaque. This plaque has a dense core of amyloid as well as a surrounding halo of deposits.

A Lewy body in the substantia nigra of a patient with Parkinson disease contains accumulations of abnormal filaments made up of α-synuclein, among other proteins. Like tau, α-synuclein is a normal soluble constituent of the cell. But in Parkinson disease it becomes insoluble.

Question 60

Do these abnormal protein accumulations affect the physiology of the neurons and glia?

Answer 60

On the one hand, the accumulations may form in response to altered post-translational processing of the proteins and serve to isolate the abnormal proteins, permitting normal cell activities. On the other hand, the accumulations may disrupt cellular activities such as membrane trafficking and axonal and dendritic transport. In addition, the altered proteins themselves, aside from the aggregations, may have deleterious effects. With β-amyloid there is evidence that the peptide itself is toxic.

Question 61

In addition to serving as cytoskeleton, what other function do microtubules and actin filaments carry out?

Answer 61

In addition to serving as cytoskeleton, microtubules and actin filaments act as tracks along which organelles and proteins are rapidly driven by molecular motors.

Question 62

What are these molecular motors called and do they carry out any other functions?

Answer 62

The motors used by the actin filaments, the myosins, also mediate other types of cell motility, including extension of the cell’s processes, and the translocation of membranous organelles from the bulk cytoplasm to the region adjacent to the plasma membrane. (Actomyosin is responsible for muscle contraction.)

Question 63

Do the myosins travel in one direction faster than the other on a given microtubule?

Answer 63

Because the microtubules and actin filaments are polar, each motor drives its organelle cargo in only one direction.

Question 64

As already mentioned, microtubules are arranged in parallel in the axon with positive ends pointing away from the cell body and negative ends facing the cell body. What does this orientation allow for cell organelles?

Answer 64

This regular orientation permits some organelles to move toward nerve endings and others to move away from nerve endings, the direction being determined by the specific type of molecule motor, thus maintaining the distinctive distribution of axonal organelles

Question 65

How can the microtubules explain why the cytoplasm of the cell body and the dendrites are similar?

Answer 65

In dendrites, microtubules with opposite polarities are mixed together, explaining why the organelles of the cell body and dendrites are similar.

Question 66

In neurons where are most of the proteins made? Give examples of substances synthesised here

Answer 66

In neurons most proteins are made in the cell body from mRNAs in the cell body. Important examples are synthesis of neurotransmitter biosynthetic enzymes, synaptic vesicle membrane components, and neuro-secretory peptides.

Question 67

What part of the neuron are these transport mechanisms most crucial for?

Answer 67

Because axons and terminals often lie at great distances from the cell body, transport mechanisms are crucial for sustaining the function of these remote regions. For example, in a motor neuron that innervates a muscle of the leg in humans, the distance of the nerve terminal from the cell body can exceed 10,000 times the cell-body diameter.

Question 68

Why can’t passive diffusion be used to deliver vesicles etc down the axon to the synapse?

Answer 68

Passive diffusion is far too slow to deliver vesicles, particles, or even single macromolecules over this great distance. Membrane and secretory products formed in the cell body must be actively transported to the end of the axon.

Question 69

Today we know that the axoplasmic flow ( axoplasm in the nerve accumulated with time on the proximal side of the ligature) Weiss observed consists of two discrete mechanisms. What mechanisms are these?

Answer 69

Membranous organelles move toward terminals (anterograde direction) and back toward the cell body (retrograde direction) by fast axonal transport, a form of transport that is faster than 400 mm per day in warm-blooded animals.

In contrast, cytosolic and cytoskeletal proteins move only in the anterograde direction by a much slower form of transport, slow axonal transport.

Question 70

How have these transport mechanisms been utilised by neurobiologists to study the brain?

Answer 70

Because these mechanisms all operate along axons, they have been used by neuroanatomists to trace the axon distribution of neurons

Question 71

Large membranous organelles are carried to and from the axon terminals by fast transport. Give some examples of what is included under this category

Answer 71

These organelles include synaptic vesicle precursors, large dense-core vesicles, mitochondria, elements of the smooth endoplasmic reticulum, as well as protein particles carrying RNAs.

Question 72

What does it mean to say that the fast transport process is saltatory?

Answer 72

Direct microscopic analysis reveals that fast transport occurs in a stop-and-start (saltatory) fashion along linear tracks of microtubules aligned with the main axis of the axon.

Question 73

Why is the fast transport process carried out in a saltatory fashion?

Answer 73

The saltatory nature of the movement results from the periodic dissociation of an organelle from the track or from collisions with other particles.

Question 74

What did early experiments on dorsal root ganglion cells show about the dependencies of anterograde fast transport?

Answer 74

Early experiments on dorsal root ganglion cells showed that anterograde fast transport depends critically on ATP, is not affected by inhibitors of protein synthesis (once the labeled amino acid injected is incorporated), and does not depend on the cell body, because it occurs in axons severed from their cell bodies. In fact, active transport can occur in reconstituted cell-free axoplasm.

Question 75

Microtubules provide an essentially stationary track on which specific organelles can be moved by molecular motors. Why is it thought that microtubules are involved in fast transport?

Answer 75

The idea that microtubules are involved in fast transport emerged from the finding that certain alkaloids that disrupt microtubules and block mitosis, which depends on microtubules, also interfere with fast transport.

Question 76

How were molecular motors first visualised?

Answer 76

Molecular motors were first visualized in electron micrographs as cross bridges between microtubules and moving particles

Question 77

What are anterograde molecular motors [composed of]?

Answer 77

The motor molecules for anterograde transport (toward the positive end of microtubules) are kinesin and a variety of kinesin-related proteins.

Question 78

What are kinesins?

Answer 78

The kinesins represent a large family of adenosine triphosphatases (ATPase), each of which transports different cargoes. Kinesin is a heterotetramer composed of two heavy chains and two light chains. Each heavy chain has three domains: (1) a globular head (the ATPase domain) that acts as the motor when attached to microtubules, (2) a coiled-coil helical stalk responsible for dimerisation with the other heavy chain, and (3) a fan-like carboxyl-terminus that interacts with the light chains.

Question 79

What is endocytosis?

Answer 79

Endocytosis is the process by which cells take in substances from outside of the cell by engulfing them in a vesicle. These can include things like nutrients to support the cell or pathogens that immune cells engulf and destroy.

Question 80

What organelles are primarily moved by retrograde fast transport?

Answer 80

The organelles moved by retrograde fast trans- port are primarily endosomes generated by endocytic activity at nerve endings, mitochondria, and elements of the endoplasmic reticulum.

Question 81

What occurs to many of the organelles associated with retrograde fast transport?

Answer 81

Many of these components degrade in lysosomes.

Question 82

Apart from transporting organelles, what other important function does retrograde fast transport have?

Answer 82

Retrograde fast transport also delivers signals that regulate gene expression in the neuron’s nucleus. For example, activated growth factor receptors are taken up into vesicles at nerve endings and carried back along the axon to their site of action in the nucleus. Transport of transcription factors informs the gene transcription apparatus in the nucleus of conditions in the periphery.

Question 83

When is retrograde transport of these transcription apparatus molecules most important?

Answer 83

Retrograde transport of these molecules is especially important during nerve regeneration and axon regrowth.

Question 84

How can retrograde transport be disadvantageous?

Answer 84

Certain toxins (tetanus toxin) as well as pathogens (herpes simplex, rabies, and polio viruses) are also transported toward the cell body along the axon.

Question 85

Compare the speed of antergrade transport to that of retrograde transport

Answer 85

The rate of retrograde fast transport is approximately one-half to two-thirds that of anterograde fast transport.

Question 86

What is used as a motor in retrograde transport and what filament is it transported on?

Answer 86

As in anterograde transport, particles move along microtubules. The motor molecule for retrograde transport is a microtubule-associated ATPase called MAP-1C.

Question 87

Describe the structure of the MAP-1C molecule

Answer 87

This molecule is similar to the dyneins in cilia and flagella of other cells and consists of a multimeric protein complex with two globular heads on two stalks connected to a basal structure. The globular heads attach to microtubules and act as motors, moving toward the negative end of the polymer. As with kinesin, the other end of the complex attaches to the organelle being moved.

Question 88

What else do microtubules transport regarding genomics?

Answer 88

Microtubules also transport mRNAs and ribosomal RNA carried in particles formed with RNA-binding proteins.

Question 89

Have these RNA-binding proteins been found in vertebrates or invertebrates and what do they include?

Answer 89

These proteins have been characterized in both vertebrate and invertebrate nervous systems and include the cytoplasmic polyadenylation element binding protein (CPEB), the fragile X protein, Hu proteins, NOVA, and Staufen.

Question 90

To what extent are these RNA-binding proteins important? Give examples

Answer 90

The activities of these proteins are critical. Humans with mutations in the fragile X gene are mentally retarded and have spinal defects. For example, CPEB keeps select mRNAs dormant during transport from the cell body to nerve endings; once there (upon stimulation), the binding protein can facilitate the local translation of the RNA by mediating polyadenylation and activation of the messenger.

Question 91

What is meant by polyadenation? **

Answer 91

Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In eukaryotes, polyadenylation is part of the process that produces mature mRNA for translation.

Question 92

How were CPEB and Staufen discovered?

Answer 92

Both CPEB and Staufen were discovered in Drosophila (genus of flies) where they maintain maternal mRNAs dormant in unfertilised eggs and, upon fertilisation, distribute and localise mRNA to various regions of the dividing embryo.

Question 93

To what extent is mRNA transported to the dendritic nerve terminals of neurons?

Answer 93

Proteins, ribosomes, and mRNA are concentrated at the base of dendritic spines. Only a select group of mRNA are transported to the nerve terminals. These include mRNA for actin- and cytoskeletal- associated proteins MAP2 and the α-subunit of the Ca2+/calmodulin-dependent protein kinase.

Question 94

What spurs the translation of this RNA in the dendrites and what is it suggested this is important for?

Answer 94

They are translated in the dendrites in response to activity in a presynaptic neuron. This local protein synthesis is thought to be important in sustaining the molecular changes at the synapse that underlie long-term memory and learning.

Likewise, the mRNA for myelin basic protein is transported to the distant ends of the oligodendrocytes, where it is translated as the myelin sheath grows.

Question 95

What is carried in slow axonal transport and how fast in anterograde transport in comparison to retrograde transport?

Answer 95

Cytosolic proteins and cytoskeletal proteins are moved from the cell body by slow axonal transport. Slow transport occurs only in the anterograde direction.

Question 96

Describe the kinetic components involved in slow axonal transport

Answer 96

Slow transport consists of at least two kinetic components that carry different proteins at different rates. The slower component travels at 0.2 to 2.5 mm per day and carries the proteins that make up the fibrillar elements of the cytoskeleton: the subunits of neurofilaments and α- and β-tubulin subunits of microtubules. The other component of slow axonal transport is approximately twice as fast as the slower. It carries clathrin, actin, and actin-binding proteins as well as a variety of enzymes and other proteins.

Question 97

Is the majority of proteins moved by the slow transport fibrous proteins or those carried by the faster kinetic component?

Answer 97

The fibrous proteins constitute approximately 75% of the total protein moved in the slower component.

Question 98

How are microtubules transported?

Answer 98

Microtubules are transported in polymerised form by a mechanism involving microtubule sliding in which relatively short preassembled microtubules move along existing microtubules.

Question 99

How is neurofilament transported?

Answer 99

Neurofilament monomers or short polymers move passively together with the microtubules because they are cross-linked by protein bridges.

Question 100

Where are the mRNAs for secretory and membrane proteins translated

Answer 100

The mRNAs for secretory and membrane proteins are translated in conjunction with the membrane of the rough endoplasmic reticulum, and their polypeptide products are processed extensively within the lumen of the endoplasmic reticulum.

Question 101

What is meant by the term cotranslational transfer?

Answer 101

Most polypeptides destined to become proteins are translocated across the membrane of the rough endoplasmic reticulum during synthesis, a process called cotranslational transfer.

Question 102

How is this cotranslational transfer possible?

Answer 102

Transfer is possible because ribosomes, the site where proteins are synthesised, attach to the cytosolic surface of the reticulum. Complete transfer of the polypeptide chain into the lumen of the reticulum produces a secretory protein (recall that the inside of the reticulum is related to the outside of the cell).

Question 103

Describe an important example of co-translational transfer

Answer 103

Important examples are the neuroactive peptides. If the transfer is incomplete, an integral membrane protein results. Because a polypeptide chain can thread its way through the membrane many times during synthesis, several membrane-spanning configurations are possible depending on the primary amino acid sequence of the protein. Important examples are neurotransmitter receptors and ion channels

Question 104

What happens the proteins once they are translated into the ER?

Answer 104

Some proteins transported into the endoplasmic reticulum remain there. Others are moved to other compartments of the vacuolar apparatus or to the plasmalemma, or are secreted into the extracellular space. Proteins that are processed in the endoplasmic reticulum are extensively modified.

Question 105

Give an example of how a protein can be modified

Answer 105

One important modification is the formation of intramolecular disulfide linkages (Cys-S-S-Cys) caused by oxidation of pairs of free sulfhydryl side chains, a process that cannot occur in the reducing environment of the cytosol. Disulfide linkages are crucial to the tertiary structure of these proteins.

Question 106

Are proteins modified by cytosolic enzymes during or after synthesis?

Answer 106

Proteins may be modified by cytosolic enzymes either during synthesis (cotranslational modification) or afterward (post-translational modification).

Question 107

Give a example of modification of proteins via cytosolic enzymes

Answer 107

N-acylation, the transfer of an acyl group to the N-terminus of the growing polypeptide chain. Acylation by a 14-carbon fatty acid myristoyl group permits the protein to anchor in membranes through the lipid chain.

Question 108

What does an acyl group consist of? **

Answer 108

An acyl group is a functional group with formula RCO- where R is bound to the carbon atom with a single bond. Typically the acyl group is attached to a larger molecule such that the carbon and oxygen atoms are joined by a double bond. Acyl groups are formed when one or more hydroxyl groups are removed from an oxoacid.

Question 109

How could a thiocylation be produced?

Answer 109

Other fatty acids can be conjugated to the sulfhydryl group of cysteine, producing a thioacylation.

Question 110

What is isoprenylation?

Answer 110

Isoprenylation is another post-translational modification important for anchoring proteins to the cytosolic side of membranes. It occurs shortly after synthesis of the protein is completed and involves a series of enzymatic steps that result in thioacylation by one of two long-chain hydrophobic polyisoprenyl moieties (farnesyl, with 15 carbons, or geranyl-geranyl, with 20) of the sulfhydryl group of a cysteine at the C-terminus of proteins.

Question 111

Break down the name hydrophobic polyisoprenyl moieties **

Answer 111

Hydrophobic substances are substances that cannot be easily dissolved in water. Poly is multiple and the prefix iso-, which stands for isomer, is commonly given to 2-methyl alkanes. In other words, if there is methyl group located on the second carbon of a carbon chain, we can use the prefix iso-. The prefix will be placed in front of the alkane name that indicates the total number of carbons (isopentane is the same as 2-methylbutane, isobutane is the same as 2-methylpropane). Preyl refers to a hydrocarbon radical or group C₅ H₈, present in prenols and in polymers of isoprene. A moiety is a part of a molecule that is given a name because it is identified as a part of other molecules as well

Question 112

What aspect of these modifications allow for transient regulation of the functions of proteins?

Answer 112

Some post-translational modifications are readily reversible and thus used to regulate the function of a protein transiently.

Question 113

What is the most common of these reversible modifications?

Answer 113

The most common of these modifications is the phosphorylation at the hydroxyl group in serine, threonine, or tyrosine residues by protein kinases. Dephosphorylation is catalysed by protein phosphatases.

Question 114

What determines which sites are phosphorylated?

Answer 114

As with all post-translational modifications, the sites to be phosphorylated are determined by particular sequences of amino acids around the residue to be modified.

Question 115

How may phosphoylation alter physiological processes?

Answer 115

Phosphorylation can alter physiological processes in a reversible fashion. For example, protein phosphorylation- dephosphorylation reactions regulate the kinetics of ion channels, the activity of transcription factors, and the assembly of the cytoskeleton.

Question 116

Name and describe another important post-translational modification

Answer 116

Still another important post-translational modification is the addition of ubiquitin, a highly conserved protein with 76 amino acids, to the ∈-amino group of specific lysine residues in the protein molecule.

Question 117

Describe the process of ubiquitination and the function in which ubiquitin carries out

Answer 117

Ubiquitination, which regulates protein degradation, is mediated by three enzymes. E1 is an activating enzyme that uses the energy of ATP. The activated ubiquitin is next transferred to a conjugase, E2, which then transfers the activated moiety to a ligase, E3. E3 alone or together with the E2 transfers the ubiquitinyl group to the lysine residue in a protein.

Question 118

How does specificity arise in the process of ubiquitination?

Answer 118

Specificity arises because a given protein molecule can only be ubiquinated by a specific E3 or combination of E3 and E2. Some E3s also require special cofactors—ubiquitination occurs only in the presence of E3 and a cofactor protein.

Question 119

What are meant by functional groups? **

Answer 119

Fuctional groups are groups of atoms which give chemicals similar properties E.g hydrocarbons are those which contain hydrogen and carbon (methane, ethane…; methene, ethene etc), alcohols are a hydroxyl group as they use a hydrogen bonded to an oxygen which is covalently bonded to the rest of the molecule

Question 120

What is monoubiquitation?

Answer 120

Monoubiquitination tags a protein for degradation in the endosoma-lysosomal system. This is especially important in endocytosis and recycling of surface receptors. Ubiquitinyl monomers are successively linked to the ∈-amino group of a lysine residue in the previously added ubiquitin moiety.

Question 121

What happens if more than 5 ubiquitins are added to the multiubiquitin chain?

Answer 121

Addition of more than five ubiquitins to the multiubiquitin chain tags the protein for degradation by the proteasome, a large complex containing multifunctional protease subunits that cleave proteins into short peptides.

Question 122

What is the ATP-ubiquitin-proteasome pathway a mechanism for and in what area(s) of the neuron is it carried out?

Answer 122

The ATP-ubiquitin-proteasome pathway is a mechanism for the selective and regulated proteolysis of proteins that operates in the cytosol of all regions of the neuron—dendrites, cell body, axon, and terminals.

Question 123

When is the ATP-ubiquitin-proteasome pathway mechanism deployed?

Answer 123

Until recently this process was thought to be primarily directed to poorly folded, denatured, or aged and damaged proteins. We now know that ubiquitin-mediated proteolysis can be regulated by neuronal activity and plays specific roles in many neuronal processes, including synaptogenesis and long-term memory storage.

Question 124

Another important protein modification is glycosylation, where does it occur and what does it result in?

Answer 124

Glycosylation occurs on amino groups of asparagine residues (N-linked glycosylation) and results in the addition en bloc of complex polysaccharide chains (long chain polymeric carbohydrates).

Question 125

Describe the rest of the process of glycosylation

Answer 125

These chains are then trimmed within the endoplasmic reticulum by a series of reactions controlled by chaperones, including heat shock proteins, calnexin, and calreticulin. Because of the great chemical specificities of oligosaccharide moieties, these modifications can have important implications for cell function. For example, cell-to-cell interactions that occur during development rely on molecular recognition between glycoproteins on the surfaces of the two interacting cells.

Question 126

A given protein can have somewhat different oligosaccharide chains. What implication does this have for glycosylation?

Answer 126

Because a given protein can have somewhat different oligosaccharide chains, glycosylation can diversify the function of a protein. It can increase the hydrophilicity (extent to which it is attracted to water molecules and tends to be dissolved by water) of the protein (useful for secretory proteins), fine-tune its ability to bind macromolecular partners, and delay its degradation.

Question 127

What is an interesting post-translational modification of mRNA?

Answer 127

An interesting post-translational modification of mRNA is RNA interference (RNAi), the targeted destruction of double-stranded RNAs. This mechanism, which is believed to have arisen to protect cells against viruses and other rogue fragments of nucleic acids, shuts down the synthesis of any targeted protein.

Question 128

What is meant by an oligomer? **

Answer 128

A molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers

Question 129

Describe the process of RNA interference (RNAi)

Answer 129

Double-stranded RNAs are taken up by an enzyme complex that cleaves the molecule into oligomers. The RNA sequences are retained by the complex. As a result, any homologous hybridising RNA strands, either double- or single-stranded, will be destroyed. The process is regenerative: The complex retains a hybridising fragment and goes on to destroy another RNA molecule until none remain in the cell.

Question 130

What is the physiological role of RNAi?

Answer 130

Although the physiological role of RNA interference (RNAi) in normal cells is unclear, transfection or injection of RNAi into cells is of great research and clinical importance

Question 131

Where do proteins go from the endoplasmic reticulum?

Answer 131

Proteins from the endoplasmic reticulum are carried in transport vesicles to the Golgi complex where they are modified and then moved to synaptic terminals and other parts of the plasmalemma.

Question 132

How does the golgi complex appear?

Answer 132

The Golgi complex appears as a grouping of membranous sacks aligned with one another in long ribbons.

Question 133

To what extent is the process of transporting vesicles between stations of the secretory and endocytic pathways generalisable across species?

Answer 133

The mechanism by which vesicles are transported between stations of the secretory and endocytic pathways is remarkably conserved from simple unicellular prokaryotes (yeast) to neurons and glia of multicellular organisms.

Question 134

How do transport vesicles form?

Answer 134

Transport vesicles develop from membrane, beginning with the assembly of proteins that form coats, or coat proteins, at selected patches of the cytosolic surface of the membrane.

Question 135

What function does the coat carry out ?

Answer 135

A coat has two functions. It forms rigid cage-like structures that produce evagination of the membrane into a bud shape and it selects the protein cargo to be incorporated into the vesicles.

Question 136

Name and describe three different types of coats

Answer 136

Clathrin coats assist in evaginating Golgi complex membrane and plasmalemma during endocytosis. Two other coats, COPI and COPII, cover transport vesicles that shuttle between the endoplasmic reticulum and the Golgi complex.

Question 137

What happens to the coats after free vesicles form?

Answer 137

Coats usually are rapidly dissolved once free vesicles have formed.

Question 138

What is meant by a secretory protein? **

Answer 138

A secretory protein is any protein, whether it be endocrine or exocrine, which is secreted by a cell. Secretory proteins include many hormones, enzymes, toxins, and antimicrobial peptides.

Question 139

What is meant by the terms endocytosis and exocytosis? **

Answer 139

While some molecules can diffuse across a membrane or be transported across via membrane bound proteins (e.g aquaporins or the glucose transporter). For transport of a lot of molecules or one very big molecule, cells use endocytosis and exocytosis to transport material in and out of the cell respectively. Endocytosis is a process that cells use to engulf extracellular material, exocytosis is a process where cells expel material into the extracellular space.

Question 140

Give examples of types of molecules and their aptitudes in crossing the cell membrane **

Answer 140

Small + non polar (e.g O2, CO2) can pass rapidly through the cell membrane.

Small + polar molecules such as water can cross as well but pretty slowly

Large + non-polar molecules (e.g vitamin A) are also very slow to cross the membrane

Large + Polar molecules (e.g glucose) and
Highly polar + charged ions (e.g Na+, K+, Cl- or amino acids) are all highly unlikely to get across a cell membrane on their own. They therefore get across the membrane using transport proteins

Question 141

Name and briefly describe the three types of endocytosis **

Answer 141

Phagocytosis: Used by white blood cells to ‘eat’ (phago) debris, bacteria and dead cells.

Pinocytosis: Cell plasma membrane invaginates to ‘drink’ (Pino) non-specific solutes.

Receptor-mediated endocytosis: Endocytosis involving special receptor proteins on the cell membrane

Question 142

Describe the process of phagocytosis **

Answer 142

It is a process carried out by white blood cells such as macrophages and neutrophils. If a macrophage encounters a streptococcus (infectious bacteria), the streptococcus would attach to macrophage receptors on the cells surface. The macrophage then extends arm-like projections around the strep and engulfs the strep slowly into the membrane which evaginates to form a vesicle. The vesicle then separates from the cell membrane forming a phagosome.

During this step, an electric pump uses ATP to pump protons into the phagosome to lower the PH. In the cytoplasm the phagosome encounters a lysosome which contains digestive enzymes. The phagosome and the lysosome merge together along with their contents, creating a structure known as a phagolysosome. Inside this, lysosomal enzymes start destroying the bacteria with the aid of an acidic PH. Afterwards the lysosome heads to the cell membrane to expel the leftovers into the extracellular space.

Question 143

Describe the process of Pinocytosis **

Answer 143

Cell plasma membrane invaginates to form a small cup around the portion of extracellular fluids and solutes that are not dissolved in it. The edges of the cup then come together, forming a vesicle. Unlike phagocytosis, pinocytosis is a non-specific way to take in solutes. Once inside the cell, motor proteins like kinesin or dynein carry the pinocytosis vesicle using ATP deeper into the cytosol. The vesicle slowly releases the extracellular fluid and solutes into the cytosol.

Question 144

Why is the vesicle in pinocytosis not considered a phagosome? **

Answer 144

Since the cell is not really ‘eating’ anything other than the occasional solute, the result is not a phagosome but merely a vesicle. The vesicle is also much smaller than a phagosome.

Question 145

Describe the process of receptor-mediated endocytosis **

Answer 145

Some molecules are taken into the cell with the assistance of special receptor proteins on the cell membrane. For example transferrin, an iron binding protein, or low density lipoproteins (LDL) which contain cholesterol. On the surface of the cell membrane there are indented pits which have specific receptors for molecules like LDL. These pits are covered on the intracellular side of the cell membrane by a layer of clathrin pits so they’re also called coated pits. Once LDL binds to a receptor in a pit, the edges of the pit start coming together. At the same time, the clathrin proteins inside the cell link up together like a shell around the vesicle. Once the vesicle pinches off from the cell membrane, the clathrin proteins detach from it and go back to the cell membrane.

Inside the cell, the vesicle merges with an organelle called an endosome. Similarly to lysosomes they merge with ingested vesicles but they can also separate the LDL particle from the LDL receptor it’s bound to. This is because the endosome has a proton pump that uses ATP to generate a low PH within which causes the LDL to separate from the receptor. The vesicle then splits into a vesicle with all of the LDL and one with all of the receptors. The one with the LDL goes to a lysosome for digestion while the one with the receptors goes back to the cell membrane. This is called receptor recycling

Question 146

Describe the process of exocytosis **

Answer 146

Exocytosis takes place in the golgi apparatus which takes the proteins, lipids and hormones generated in the rough and smooth ER and packages them into a vesicle that can be ziplined around the cell using the cytoskeleton. Secretory vesicles move structures out of the cell with the help of motor proteins such as kinesin or dynein using ATP as fuel. The vesicle moves towards the cells surface, fuses with the cell membrane and ruptures on its external side, spilling its contents into the extracellular space.

Question 147

What happens when the free vesicle meets the target membrane?

Answer 147

The fusion of vesicles with the target membrane is mediated by a cascade of molecular interactions, the most important of which is the reciprocal recognition of small proteins on the cytosolic surfaces of the two interacting membranes: vesicular soluble N-ethylmaleimide-sensitive factor attachment protein receptors (v-SNAREs) and t-SNAREs (target-membrane SNAREs).

Question 148

Describe what happens once the vesicles reach the golgi complex

Answer 148

Vesicles from the endoplasmic reticulum arrive at the cis side of the Golgi complex (the aspect facing the nucleus) and fuse with its membranes to deliver their contents into the Golgi complex. These proteins travel from one Golgi compartment (cisterna) to the next, from the cis to the trans side, undergoing a series of enzymatic reactions. Each Golgi cisterna or set of cisternae is specialised for a particular type of reaction. Several types of protein modifications, some of which begin in the endoplasmic reticulum, occur within the Golgi complex proper or within the transport station adjacent to its trans side, the trans-Golgi network (the aspect of the complex typically facing away from the nucleus toward the axon hillock).

Question 149

What kind of modifications can occur to proteins in the trans-golgi network?

Answer 149

These modifications include the addition of N-linked oligosaccharides, O-linked (on the hydroxyl groups of serine and threonine) glycosylation, phosphorylation, and sulfation.

Question 150

Where do (1) soluble and (2) membrane-bound proteins that travel through the Golgi complex emerge from the trans-Golgi network?

Answer 150

Both soluble and membrane-bound proteins that travel through the Golgi complex emerge from the trans-Golgi network in a variety of vesicles that have different molecular compositions and destinations.

Question 151

What kind of proteins are transported from the trans-Golgi network?

Answer 151

Proteins transported from the trans-Golgi network include secretory products as well as newly synthesised components for the plasmalemma, endosomes, and other membranous organelles.

Question 152

One class of vesicles carries newly synthesised plasmalemmal proteins and proteins that are continuously secreted. What name is given to this kind of secretion and name an important type of these vesicles

Answer 152

One class of vesicles carries newly synthesised plasmalemmal proteins and proteins that are continuously secreted (constitutive
secretion). These vesicles fuse with the plasmalemma in an unregulated fashion. An important type of these vesicles delivers lysosomal enzymes to late endosomes (primarily intracellular sorting organelles).

Question 153

How may other vesicles carry out secretion?

Answer 153

Still other classes of vesicles carry secretory proteins that are released by an extracellular stimulus (regulated secretion).

Question 154

Describe one type of vesicle which engages in regulated secretion

Answer 154

One type stores secretory prod- ucts, primarily neuroactive peptides in high concen- trations. Called large dense-core vesicles because of their electron-dense (osmophilic) appearance in the electron microscope, these vesicles are similar in function and biogenesis to peptide-containing granules of endocrine cells.

Question 155

What are large dense-core vesicles found in the neuron?

Answer 155

Large dense-core vesicles are targeted primarily to axons but can be seen in all regions of the neuron. They accumulate in the cytoplasm just beneath the plasma membrane and are highly concentrated at axon terminals, where they undergo Ca2+-regulated exocytosis. The optimal stimulus for their secretion is a train of action potentials.

Question 156

What is an important unanswered question about synaptic vesicles?

Answer 156

An important, but as yet unanswered, question is how synaptic vesicles—the small lucent vesicles responsible for the rapid release of neurotransmitter at axon terminals—reach the terminals.

Question 157

What is the current thinking on the synaptic vesicle problem?

Answer 157

It is thought that proteins that make up synaptic vesicles are carried to endosomes and the plasmalemma of axon terminals in large precursor vesicles from the trans- Golgi network. Once at the terminals the proteins are processed into synaptic vesicles as they pass through endosomes during the exocytosis/recycling process. The neurotransmitter molecules stored in synaptic vesicles are released by exocytosis regulated by Ca2+ influx through channels close to the release site.

Question 158

How is vesicular traffic toward the cell surface balanced out? WHy is this essential? (3)

Answer 158

Vesicular traffic toward the cell surface is continuously balanced by endocytic traffic from the plasmalemma to internal organelles. This traffic is essential for maintaining the area of the plasmalemma in a steady state. It can alter the activity of many important regulatory molecules on the cell surface (eg, by removing receptors and adhesion molecules). It also removes nutrients and molecules, such as expendable receptor ligands and damaged membrane proteins, to the degradative compartments of the cells. Finally, it serves to recycle synaptic vesicles at nerve terminals

Question 159

What is meant by receptor-mediated endocytosis? (We were ahead of the curve :p)

Answer 159

A significant fraction of endocytic traffic is carried in clathrin-coated vesicles. The clathrin coat interacts selectively through transmembrane receptors with extracellular molecules that are to be taken up into the cell. For this reason clathrin-mediated uptake is often referred to as receptor-mediated endocytosis. The vesicles eventually shed their clathrin coats and fuse with the early endosomes, in which proteins to be recycled to the cell surface are separated from those destined for other intracellular organelles.

Question 160

How may patches of the plasmalemma also be recycled?

Answer 160

Patches of the plasmalemma can also be recycled through larger, uncoated vacuoles that also fuse with early endosomes (bulk endocytosis).

Question 161

Describe the role of oligodendrocytes and Schwann cells

Answer 161

A major function of oligodendrocytes and Schwann cells is to provide the insulating material that allows rapid conduction of electrical signals along the axon. These cells produce thin sheets of myelin that wrap con- centrically, many times, around the axon.

Question 162

To what extent is the myelin produced by oligodendrocytes and schwann cells similar?

Answer 162

Central nervous system myelin, produced by oligodendrocytes, is similar, but not identical to peripheral nervous system myelin, produced by Schwann cells. One Schwann cell produces a single myelin sheath for one segment of one axon, whereas one oligodendrocyte produces myelin sheaths for segments of as many as 30 axons

Question 163

How thick is a myelin sheath typically? (In regards to layers)

Answer 163

The number of layers of myelin on an axon is proportional to the diameter of the axon—larger axons have thicker sheaths. Axons with very small diameters are not myelinated.

Question 164

Comment on the speed at which action potentials travel in these smaller on-myelinated axons

Answer 164

Nonmyelinated axons conduct action potentials much more slowly than do myelinated axons because of their smaller diameter and lack of myelin insulation

Question 165

What are the regular lamellar structure and biochemical com- position of the sheath a consequence of?

Answer 165

The regular lamellar structure and biochemical com- position of the sheath are consequences of how myelin is formed from the glial plasma membrane. In the development of the peripheral nervous system, before myelination takes place, the axon lies within a trough formed by Schwann cells. Schwann cells line up along the axon at regular intervals that become the myelinated segments of axon.

The external membrane of each Schwann cell surrounds the axon to form a double membrane structure called the mesaxon, which elongates and spirals around the axon in concentric layers. As the axon is ensheathed, the cytoplasm of the Schwann cell is squeezed out to form a compact lamellar structure.

Question 166

What is between these regularly spaced myelin sheaths and what function do they play out? Name the mechanism at play

Answer 166

The regularly spaced segments of myelin sheath are separated by unmyelinated gaps, called nodes of Ranvier, where the plasma membrane of the axon is exposed to the extracellular space for approximately 1 μm. This arrangement greatly increases the speed at which nerve impulses are conducted (up to 100 m/s in humans) because the signal jumps from one node to the next, a mechanism called saltatory conduction.

Question 167

Why are the nodes easily excited?

Answer 167

Nodes are easily excited because they have a low threshold. In the axon membrane at the nodes the density of Na+ channels, which generate the action potential, is approximately 50 times greater than in myelin-sheathed regions of membrane. Several cell adhesion molecules in the paranodal regions keep the myelin boundaries stable.

Question 168

Describe the composition of myelin in the central nervous system

Answer 168

Myelin has bimolecular layers of lipid interspersed between protein layers. Its composition is similar to that of the plasmalemma, consisting of 70% lipid and 30% protein with high concentrations of cholesterol and phospholipid.

In the central nervous system myelin has two major proteins: myelin basic protein, a small, positively charged protein that is situated on the cytoplasmic surface of compact myelin, and proteolipid protein, a hydrophobic integral membrane protein.

Question 169

What roles do these proteins in CNS myelin carry out?

Answer 169

Presumably, both provide structural stability for the sheath. Both have also been implicated as important autoantigens against which the immune system can react to produce the demyelinating disease, multiple sclerosis.

Question 170

Describe the protein composition of myelin in the peripheral nervous system

Answer 170

In the peripheral nervous system myelin contains a major protein, P0 , as well as the hydrophobic protein PMP22.

Question 171

What do autoimmune responses to peripheral nervous system myelin proteins produce?

Answer 171

Autoimmune reactions to these proteins produce a demyelinating peripheral neuropa- thy, the Guillain-Barré syndrome.

Question 172

What can mutations in myelin protein genes cause?

Answer 172

Mutations in myelin protein genes also cause a variety of demyelinating diseases in both peripheral and central axons. Demyelination slows down, or even stops, conduction of the action potential in an affected axon, because it allows electrical current to leak out of the axonal membrane. Thus, demyelinating diseases have devastating effects on neuronal circuits in the brain, spinal cord, and peripheral nervous system.

Question 173

Describe the process of peripheral nerve myelination

Answer 173

A peripheral nerve fiber is myelinated by a Schwann cell in several stages. In stage 1 the Schwann cell surrounds the axon. In stage 2 the outer aspects of the plasma membrane have become tightly apposed in one area. This membrane fusion reflects early myelin membrane formation. In stage 3 several layers of myelin have formed because of continued rotation of the Schwann cell cytoplasm around the axon. In stage 4 a mature myelin sheath has formed; much of the Schwann cell cytoplasm has been squeezed out of the innermost loop.

Question 174

What cells constitute nearly half the number of brain cells?

Answer 174

Astrocytes are star-shaped glia found in all areas of the brain; indeed, they constitute nearly half the number of brain cells.

Question 175

What roles do astrocytes play? (3)

Answer 175

They play important roles in nourishing neurons and in regulating the concentrations of ions and neurotransmitters in the extracellular space. Astrocytes and neurons also communicate with each other to modulate synaptic signalling in ways that are still poorly understood.

Question 176

Describe the relative location and shape of astrocytes. How does this relative location assist them in the role they carry out?

Answer 176

Astrocytes have large numbers of thin processes that enfold all the blood vessels of the brain, and ensheath synapses or groups of synapses.

By their intimate physical association with synapses, often closer than 1 μm, astrocytes are positioned to regulate extra- cellular concentrations of ions, neurotransmitters, and other molecules

Question 177

Describe the first recognised physiological role in how astrocytes regulate axonal conduction and synaptic activity

Answer 177

The first recognised physiological role was that of K+ buffering. When neurons fire action potentials they release K+ ions into the extracellular space. Because astrocytes have high concentrations of K+ channels in their membranes, they can act as spatial buffers: They take up K+ at sites of neuronal activity, mainly synapses, and release it at distant contacts with blood vessels. Astrocytes can also accumulate K+ locally within their cytoplasmic processes along with Cl− ions and water.

Question 178

What downside may the accumulation of ions and water in astrocytes have?

Answer 178

Unfortunately, accumulation of ions and water in astrocytes can contribute to severe brain swelling after head injury.

Question 179

Give an example of how astrocytes also regulate neurotransmitter concentrations in the brain.

Answer 179

High-affinity (the degree to which a substance tends to combine with another) transporters located in the astrocyte’s plasma membrane rapidly clear the neurotransmitter glutamate from the synaptic cleft. Once within the glial cell, glutamate is converted to glutamine by the enzyme glutamine synthetase. Glutamine is then transferred to neurons, where it serves as an immediate precursor of glutamate. Astrocytes also degrade dopamine, norepinephrine, epinephrine, and serotonin.

Question 180

What does interference with these astrocyte uptake mechanisms of glutamate lead to?

Answer 180

Interference with these uptake mechanisms results in high concentrations of extracellular glutamate that can lead to the death of neurons, a process termed excitotoxicity.

Question 181

How do astrocytes sense when neurons are active?

Answer 181

Astrocytes sense when neurons are active because they are depolarised by the K+ released by neurons and have neurotransmitter receptors similar to those of neurons.

Question 182

Give an example of what can happen when neurotransmitter receptors similar to those of neurons are activated via an action potential

Answer 182

Bergmann glia in the cerebellum express glutamate receptors. Thus, the glutamate released at cerebellar synapses affects not only post- synaptic neurons but also astrocytes near the synapse. The binding of these ligands to glial receptors increases the intracellular free Ca2+ concentration, which has several important consequences. The processes of one astrocyte connect to those of neighbouring astrocytes through gap junctions, allowing transfer of ions and small molecules between many cells. An increase in free Ca2+ within one astrocyte increases Ca2+ concentrations in adjacent astrocytes. This spread of Ca2+ through the astrocyte network occurs over hundreds of micrometers. It is likely that this Ca2+ wave modulates nearby neuronal activity by triggering the release of nutrients and regulating blood flow. An increase in Ca2+ in astrocytes leads to the secretion of signals that enhance synaptic function, but the specific molecular components of these signals are not understood.

Question 183

How else are astrocytes important in regards to synapses?

Answer 183

Astrocytes also are important for the development of synapses. They prepare the surface of the neuron for synapse formation and stabilise newly formed synapses.

Question 184

Give an example of how astrocytes promote the formation of new synapses

Answer 184

Astrocytes secrete substances called thrombospondins that promote the formation of new synapses. In pathological states, such as chromatolysis produced by axonal damage, astrocytes and presynaptic terminals temporarily retract from the damaged postsynaptic cell bodies. Astrocytes release neurotrophic and gliotrophic factors that promote the development and survival of neurons and oligodendrocytes.

Question 185

How do astrocytes also protect other cells in the brain?

Answer 185

Astrocytes also protect other cells from the effects of oxidative stress. For example, the glutathione peroxidase in astrocytes detoxifies toxic oxygen free radicals released during hypoxia, inflammation, and neuronal degeneration.

Question 186

Describe the role astrocytes play in the blood circulation system

Answer 186

Astrocytes ensheath small arterioles and capillaries throughout the brain, forming contacts between the ends of astrocyte processes and the basal lamina around endothelial cells. The central nervous system is sequestered from the general circulation so that macromolecules in the blood do not passively enter the brain and spinal cord (the “blood-brain barrier”). The barrier is largely the result of tight junctions between endothelial cells and cerebral capillaries, a feature not shared by capillaries in other parts of the body. Nevertheless, endothelial cells have a number of transport properties that allow some molecules to pass through them into the nervous system. Because of the intimate astrocyte–blood vessel contacts, the transported molecules, such as glucose, come into contact with and can be taken up by astrocyte end-feet.

Question 187

What is epithelium? **

Answer 187

What is the epithelium? The epithelium is a type of body tissue that forms the covering on all internal and external surfaces of your body, lines body cavities and hollow organs and is the major tissue in glands

Question 188

What is meant by neuroepithelium? **

Answer 188

A type of epithelium containing sensory nerve endings and found in certain sense organs (e.g. the retina, the inner ear, the nasal membranes, and the taste buds).

Question 189

Cells of the ependyma and choroid plexus are derived from immature neuroepithelium.

What are these? (ependyma and choroid plexus)

Answer 189

The ependyma is the thin neuroepithelial (simple columnar ciliated epithelium) lining of the ventricular system of the brain and the central canal of the spinal cord. The ependyma is one of the four types of neuroglia in the central nervous system.

The choroid plexus is a network of blood vessels in each ventricle of the brain, producing the cerebrospinal fluid.

Question 190

What function does the ependyma and choroid plexus carry out?

Answer 190

The ependyma, a single layer of ciliated cuboidal cells, lines all the ventricles of the brain, helping to move cerebrospinal fluid through the ventricular system. At several places in the lateral and fourth ventricles the ependyma is continuous with cells of the choroid plexus, which covers thin blood vessels that project into the ventricles. These choroid plexus epithelial cells filter plasma from the blood and secrete this ultrafiltrate as cerebrospinal fluid.

Question 191

How do microglia differ from neurons, astrocytes, and oligodendrocytes?

Answer 191

Unlike neurons, astrocytes, and oligodendrocytes, microglia do not belong to the neuroectodermal lineage. Instead they derive from bone marrow.

Question 192

Where in the brain are microglia found?

Answer 192

Entering the central nervous system early in development, they reside in all regions of the brain throughout life.

Question 193

What functions do microglia carry out?

Answer 193

Their functions are not well under- stood, although they probably play an important role in immunological surveillance in the CNS, poised to react to foreign invaders.

Question 194

Why is it thought that microglia carry out this immunological role?

Answer 194

Of all of the cells in the central nervous system, microglia are the best at processing and presenting antigens to lymphocytes and secreting cytokines and chemokines during inflammation. Thus they serve to bring lymphocytes, neutrophils, and monocytes into the central nervous system and expand the lymphocyte population, important immunological activities in infection, stroke, and immune-mediated demyelinating disease. Microglia can also become macrophages, clearing debris after infarcts (strokes) or other degenerative neurological disorders.

Question 195

What are cytokines? **

Answer 195

Cytokines are a broad and loose category of small proteins important in cell signalling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research.

Question 196

What are chemokines? **

Answer 196

The chemokines (or chemotactic cytokines) are a large family of small, secreted proteins that signal through cell surface G protein‐coupled heptahelical chemokine receptors. They are best known for their ability to stimulate the migration of cells, most notably white blood cells (leukocytes).

Question 197

Describe the regions adjacent to the nodes of ranvier

Answer 197

Regions on both sides of a node of Ranvier are rich in stable contacts between myelinating cells and the axon, to ensure that the nodes do not move or change in size and to restrict the localisation of K+ and Na+ channels in the axon. Potassium permeable channels and the adhesion protein Caspr2 are concentrated in the juxtaparanode.

Paranodal loops (PNL) of Schwann cell or oligodendrocyte cytoplasm form a series of stable junctions with the axon. The paranode region is rich with adhesion proteins such as Caspr2, contactin, and neurofascin (NF155). At the nodes in central axons, perinodal astroglial processes (PNP) contact the axonal membrane, which is enormously rich with Na+ channels. This localisation of Na+ permeability is a major basis for the saltatory conduction in myelinated axons. The membrane-cytoskeletal linker ankyrin G (ankG) and the cell adhesion molecules NrCAM and NF186 are also concentrated at the nodes.

See docs for diagram

Question 198

What can defective myelination result in?

Answer 198

Because in myelinated axons normal conduction of the nerve impulse depends on the insulating properties of the myelin sheath defective myelin can result in severe disturbances of motor and sensory function.

Question 199

What is the cause of many diseases that affect myelin?

Answer 199

Many diseases that affect myelin, including some animal models of demyelinating disease, have a genetic basis. The shiverer (or shi) mutant mice have tremors and frequent convulsions and tend to die young. In these mice the myelination of axons in the central nervous system is greatly deficient and the myelination that does occur is abnormal.

Question 200

The mutation that causes this disease is a deletion of five of the six exons of the gene for myelin basic protein, which in the mouse is located on chromosome 18. The mutation is recessive; a mouse develops the disease only if it has inherited the defective gene from both parents. Shiverer mice that inherit both defective genes have only approximately 10% of the myelin basic protein found in normal mice.

Describe the results of a study which investigated these mice

Answer 200

When the wild-type gene is injected into fertilised eggs of the shiverer mutant with the aim of rescuing the mutant, the resulting transgenic mice express the wild-type gene but produce only 20% of the normal amounts of MBPs. Nevertheless, myelination of central neurons in the transgenic mice is much improved. Although they still have occasional tremors, the transgenic mice do not have convulsions and have a normal life span.

Question 201

What is meant by a wild type gene? **

Answer 201

The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualised as a product of the standard “normal” allele at a locus, in contrast to that produced by a non-standard, “mutant” allele.

Question 202

What is meant by the abbreviation MAG in regards to myelin? Describe this

Answer 202

In both the central and peripheral nervous systems myelin contains a protein termed myelin-associated glycoprotein (MAG). MAG belongs to the immunoglobulin superfamily that includes several important cell surface proteins thought to be involved in cell-to-cell recognition, eg, the major histocompatibility complex of antigens, T-cell surface antigens, and the neural cell adhesion molecule (NCAM).

Question 203

What are the histocompatibility complex of antigens (HCA)? **

Answer 203

Major histocompatibility complex (MHC), group of genes that code for proteins found on the surfaces of cells that help the immune system recognise foreign substances. MHC proteins are found in all higher vertebrates. In human beings the complex is also called the human leukocyte antigen (HLA) system.

Question 204

What are glycoproteins? **

Answer 204

Glycoproteins are proteins which contain oligosaccharide chains (glycans) covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

Question 205

What is the Neural cell adhesion molecule (NCAM)? **

Answer 205

NCAM is a member of the immunoglobulin superfamily. It is a glycosylated protein expressed in most cells of the central and peripheral nervous system, muscle, heart, and gonads. NCAM is concentrated at contact sites between cells and mediates cell adhesion and recognition by intercellular homophilic interactions.

Question 206

When and where is MAG expressed? What is it’s function?

Answer 206

MAG is expressed by Schwann cells early during production of myelin and eventually becomes a component of mature (compact) myelin. Its early expression, subcellular location, and structural similarity to other surface recognition proteins suggest that it is an adhesion molecule important for the initiation of the myelination process. Two isoforms of MAG are produced from a single gene through alternative RNA splicing.

Question 207

More than half the protein in myelin i central axons is _______

Answer 207

More than half of the protein in myelin in central axons is the proteolipid protein (PLP), which has five membrane-spanning domains.

Question 208

What is the difference between Proteolipids and lipoproteins ?

Answer 208

Proteolipids differ from lipoproteins in that they are insoluble in water. Proteolipids are soluble only in organic solvents because they contain long chains of fatty acids that are covalently linked to amino acid residues throughout the proteolipid molecule. In contrast, lipoproteins are noncovalent complexes of proteins with lipids and often serve as soluble carriers of the lipid moiety in the blood.

Question 209

Many mutations of PLP are known in humans as well as in other mammals, eg, the jimpy mouse. Give an example of this in humans

Answer 209

One example is Pelizaeus-Merzbacher disease, a heterogeneous X-linked disease in humans. Pelizaeus-Merzbacher disease is a disorder that affects the brain and spinal cord. It is a type of leukodystrophy (affect the white matter of the brain) and is characterized by problems with coordination, motor skills, and learning. It is caused by an inability to form myelin due to genetic changes in the PLP1 gene.

Question 210

Where do these mutations of PLP typically occur?

Answer 210

Almost all PLP mutations occur in a membrane-spanning domain of the molecule.

Question 211

What is observed in animals with mutated PLP? What could this suggest?

Answer 211

Mutant animals have reduced amounts of (mutated) PLP, hypomyelination (unable to produce myelin at normal levels), and degeneration and death of oligodendrocytes. These observations suggest that PLP is involved in the compaction of myelin.

Question 212

What is the major protein found in mature peripheral myelin? Where is it mainly found?

Answer 212

The major protein in mature peripheral myelin, myelin protein zero (MPZ or P0), spans the plasmalemma of the Schwann cell.

Question 213

In what regard is MPZ similar to MAG?

Answer 213

It has a basic intracellular domain and, like MAG, is a member of the immunoglobulin superfamily.

Question 214

Describe the extracellular part of the protein

Answer 214

The glycosylated extracellular part of the protein, which contains the immunoglobulin domain, functions as a homophilic adhesion protein (Attaches to an identical molecule in an adjacent cell) during myelin ensheathing by interacting with identical domains on the surface of the apposed membrane.

Question 215

What is observed in genetically engineered mice in which the function of P0 has been eliminated?

Answer 215

Genetically engineered mice in which the function of P0 has been eliminated have poor motor coordination, tremors, and occasional convulsions.

Question 216

What has observation of trembler mouse mutants led to?

Answer 216

Observation of trembler mouse mutants led to the identification of peripheral myelin protein 22 (PMP22). This Schwann cell protein spans the membrane four times and is normally present in compact myelin. PMP22 is altered by a single amino acid in the mutants. A similar protein is found in humans, encoded by a gene on chromosome 17.

Question 217

What do mutations of the PMP22 gene on chromosome 17 lead to?

Answer 217

Mutations of the PMP22 gene on chromosome 17 produce several hereditary peripheral neuropathies, while a duplication of this gene causes one form of Charcot-Marie-Tooth disease

Question 218

What are the symptoms of Charcot-Marie-Tooth disease and what does it result from (what effect of duplication)

Answer 218

Charcot-Marie-Tooth disease, the most common inherited peripheral neuropathy, and is characterised by progressive muscle weakness, greatly decreased conduction in peripheral nerves, and cycles of demyelination and remyelination. Because both duplicated genes are active, the disease results from increased production of PMP22 (a two- to three-fold increase in gene dosage).