Lecture 10: Cellular Structure of the Brain 2 Flashcards

1
Q

what is special about neurons?

A

shape and size - unique as it is dependent on where input is from, location, and where their axons have to go

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2
Q

Shape of the neuron

A

determined by connections - input/output

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3
Q

how is neuron shape maintained?

A

proteins

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4
Q

what is different between the dendrite and axon?

A

membrane proteins

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5
Q

What does the cytoskeleton help to do

A

maintain and make shapes and therefore maintaining the function of the neurons

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6
Q

what dimers bind together to form microtubules?

A

alpha and beta tubulin

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7
Q

add tubulin dimers to which end of the microtubule?

A

add tubulin dimers at the positive end to elongate axon (grows towards the end of the axon)

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8
Q

MAP-2

A

dendrite specific also the soma

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9
Q

Tau

A

dendrite and axon

enriched in distal axon

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10
Q

Microtubule uniform orientation

A

positive ends towards axonal end

microtubules are highly organised in the axons and dendrites, microtubules bound by tau in the axons which stability the structure and they also have uniform extension

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11
Q

microtubule mixed orientation

A

positives at both ends therefore both ends can extend which allows for extending and retracting

MAP2 allows for stabilising of structures in dendrites forming parallel networks

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12
Q

loss of MAPs

A

tangled microtubules which disrupts structure which disrupts cell which disrupts function

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13
Q

Material is transported down the axon via

A

microtubules (highways of the cell)

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14
Q

How was axonal transport found out about?

A

Axonal transport – 1930’s - squid neuron
Ligate axon, vesicles accumulate on soma side
Inject label into soma and watch it move down axon - moved down faster than rate of diffusion therefore realised something must actually be transporting them
The first electron microscope made in 1931.

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15
Q

Fast axonal transport

A

bidirectional (250-400mm/day)

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16
Q

Slow axonal tranport

A

anterograde (1mm/day) - transporting more structure molecules therefore do not need as fast flow as fast axonal transport

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17
Q

anterograde axonal transport carries

A

mitochondria, vesicles, membrane lipids

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18
Q

Retrograde axonal transport

A

used materials

purpose = recycle and repair, materials that need to be recycled e.g. degraded materials or nonfunctioning mitochondria

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19
Q

_______ proteins and axonal transport

A

uses motor proteins
kinesin - antero
dynein - retro

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20
Q

Motor protein for anterograde axonal transport

A

kinesin

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21
Q

motor protein for retrograde axonal transport

A

dynein

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22
Q

Kinesins vs dynein

A

Kinesins govern the majority of anterograde transport and dynein is responsible for retrograde transport, shuttling proteins back toward the cell body for recycling

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23
Q

motor protein consists of

A

motor domain, tail domain

24
Q

Motor protein - motor domain

A
contains ATPase (uses ATP) 
conserved across species
25
Motor protein - tail domain
specifies function of motor molecule diverse within/across species attaches on to the organelle/vesicles that is going to be transported
26
Cargo and motor protein tail
Cargo have distinct mechanisms to select and dock to the correct motor protein tail when you put something into a vesicle you call it a cargo the vesicle does not have a simple plasma membrane, lots of proteins associated which act as signposts/label which attach onto the motor protein which can take that organelle down to where it is required
27
Neurofilament overall function
maintain the strength and structure of neurons
28
diameter of neurofilaments
10nm
29
Neurofilament features
``` predominant cytoskeletal component ́ = intermediate filaments huge mechanical strength ́most stable of cytoskeleton ́important in structural framework - very dense and provide the structure, they are very stable and very strong ``` neurofilaments in the axon have associated proteins - extensive cross linking gives high tensile strength
30
Neurofilaments are ...
cargos of axonal transport (move along an axon as cargo on a microtubule)
31
Microfilaments made up of
actin - filamentous (F) and monomeric (G)
32
Diameter of microfilaments
3-5nm
33
features of microfilaments
dynamic = continual remodelling of actin filaments | polar - positive (barbed) and negative (pointed) ends
34
F-actin
filamentous | 2 stranded helical filament (weak covalent bonds)
35
G-actin
monomeric
36
Actin tread milling summary
In a microfilament get a net flow of newly acquired G-actin through the filament = known as actin treadmilling: -> a dynamic turnover of actin filaments while filament length is maintained Or increase / decrease length or alter the arrangement good for cell motility and keeping its shape
37
actin dynamics - elongation
add faster at positive end but also adds at negative end just not as much i.e. 3 to 1 for example
38
actin dynamics - steady state
(rapid) polymerisation at the G-actin+ATP site and depolymerisation at the ADP actin site steady state - the concentration of G actin in the cytoplasm reaches a plateu meaning a steady state level of actin dynamics, instead of actin extending on both sides it actually stays the same length (polymerises at one end and depolymerises at the other end) and it uses ATP to do this and we call this stead state level and the change of actin dynamics treadmilling
39
Microfilaments function
Actin –filamentous (F) ́ Mature neuron ́Stabilization – key role (keeping proteins in place) ́many actin binding proteins (a-actinin) ́inner plasma membrane proteins crosslink to actin ́anchors molecules, vesicles (very organised) (and receptors as well) ́in spine head - no MTs (microtubules therefore replaces their function) -> shape ́enriched at synapse, (pre and post) – shape, size and holding proteins ́ Developing neuron / plasticity ́Neurite formation, extension, branching, development of spines and synapses The functional roles for microfilaments involve cell membrane motility, endo- and exocytosis, secretion and vesicle transfer.
40
Actin binding proteins
``` Crosslinking proteins (actin-binding proteins) can arrange F-actin into distinct networks, such as actin bundles, mesh-like and gels. e.g. α-actinin, filamin ``` Actin is important: Mutation in Filamin -periventricular heterotopia, neurons do not migrate properly during the early development of the fetal brain (not having fully functioning actin means that the neurons work differently)
41
Cytoskeletal organisation of dendritic spines
actin is important in dendritic spines actin is also a part of our axonal transport because microtubules cannot get into the spines (too big) so actin replaces its role in the spines - initially on microtubule and then gets to spine so vesicle etc hops off the microtubule using a different motor protein and then actually be transported by the actin protein network into the spine, also actin has a tree like structure which means that it is important for the shape of the spine, which can extend, also important in recycling
42
Actin in the presynaptic terminal
Enriched at presynaptic terminal ́Regulates vesicle pool ́Small groups linked ́Groups attached to plasma membrane ́At periactive zone - ? Involved in vesicle recycling actin important in both pre and post synaptic terminals
43
Pools at the presyanaptic terminal
2 pools releasable pool readily releasable pool
44
Actin in the postsynaptic terminal
submembraneous actin network interlinks scaffolding proteins - organises PSD (post synaptic density) actin filaments regulate surface-receptor diffusion and the eco-endocytic trafficking of receptors to the surface actin - spine shape- transport
45
Can axonal transport go wrong?
‘... experimental studies suggest that the degeneration of terminals and axons precedes the demise of neurons which finally results in the clinical symptoms...” once recognised clinically, the damage to the axonal transport system and other features of neurons has already been done
46
Failure of axonal transport seen in
``` Defects in axonal transport and/or in the cytoskeleton are often seen in the CNS and peripheral neuropathies: Seen in ́ Alzheimer’s disease Motor neuron disease Parkinson’s disease Acquired peripheral neuropathies Diabetic neuropathies Metabolic syndromes Auto-immune diseases Alcohol abuse Anti cancer therapies ``` Symptoms of disease = late We need to know what is happening early -to develop a therapy
47
Diabetic neuropathy features
One putative mechanism of axonal damage in diabetes is impairments to axonal transport. Several alterations can contribute to the disruption of axonal transport: • alterations in the cytoskeleton • molecular motor proteins • cargo proteins • mitochondrial transport and other transport • and possibly, microglia-driven neuroinflammation
48
Summary of high uncontrolled blood glucose in body
high blood glucose in body that is uncontrolled - diabetic neuropathy - affects nerves in legs and feet
49
Diabetes and cytoskeleton
impaired cytoskeleton assembly decrease in axon calibre motor proteins fail to bind microtubules (therefore not as much transport) Impaired transport of synaptic vesicle precursors and mitochondria (?) Neuroinflammation (?) Microglia cells - pro inflammatory molecules (TNF) - affect anterograde transport (microglia become activated therefore proinflammation etc) Less neurofilaments therefore less structure
50
Hyperglycaemia in diabetes (PNS)
Excess glucose molecules allow addition of sugar molecules to protein, e.g. to tubulin and alters its function (seems to be a peripheral axonal tubulin effect, not central.)
51
Microtubules in diabetes
decrease tubulin mRNA increase in tubulin glycation increase in tau phosphorylation increase in tau cleavage
52
Microfilaments in diabetes
increase in actin glycation
53
Neurofilaments in diabetes
decrease in NF-L and NF-H mRNA increase in NF phosphorylation Loss of axonal NFs
54
Overall diabetes effects
decrease axon calibre decrease speed conduction decrease axonal tranport decrease nerve regeneration
55
alzeimers affects the
CNS
56
The changing brain of alzheimers disease
AD brain changes start decades before symptoms show (preclinical AD) cognitive problems, brain dies over time (shrinks)
57
Causes of Alzheimers disease
``` Age and gender genetic factors infections environmental factors others - obesity, diabetes lifestyle cardiovascular disease head injuries ``` central to it all is inflammation