Myelination in CNS (Week 3--Schweizer)

Question 1

Why is it good that Na+ influx is restricted just to the Nodes of Ranver?

Answer 1

1) Reduces total Na+ influx and thus amount of energy that needs to be expended to restore Na+ balance after AP
2) Reduces changes in extracellular solute concentrations (particularly important in areas of high axonal densities with high firing rates)

Question 2

How might myelination contribute to neuronal plasticiy?

Answer 2

Neuronal activity increases myelination

Animals in enriched environments have increased white matter, especially in corpus callosum

Question 3

How does myelination change over one’s lifetime?

Answer 3

Myelination does not end at birth, it increases during development and into adulthood

Could contribute to changes in cognitive ability such as language perception

Deficits in appropriate myelination might contribute to mental diseases such as schizophrenia

Question 4

Where does myelination of a neuron start?

Answer 4

Myelination is usually restricted to the axon

Starts at distal end of axon hillock with “half-node” of Ranvier

Question 5

Do other parts of the neuron ever get myelinated?

Answer 5

Cell bodies in olfactory bulb

Dendrites, although myelin sheath is very thin

Question 6

Difference in thickness of myelination in periphery vs. CNS?

Answer 6

Myelinated axons in CNS are thinner because no endoneurium, so can be very closely positioned next to each other

Question 7

Are all axons in the CNS myelinated?

Answer 7

No!

Parallel fibers in cerebellum not myelinated

Shaffer collateral fibers in hippocampus not myelinated

Question 8

In general, what do concentric layers of myelin contain?

Answer 8

Lipid bilayer

Cytoplasm (very thin)

Extracellular space (very thin)

Question 9

Composition of lipid bilayer of myelin

Answer 9

Different from other cell membranes, but all lipids found in myelin also found in other membranes and vice versa

Rich in cerebrosides and other glycosylated lipids

Few phospholipids

Little protein but most belongs to a few classes (MBP, PLP); other proteins are CNPase, MAG, OMgp

Question 10

Protein of myelin sheath

Answer 10

Myelin basic protein (MBP): cytoplasmic; majority of myelin protein with PLP

Proteolipid protein (PLP): transmembrane and might hold stacks of membrane together; majority of myelin protein with MBP

2’:3’-cyclic-nucleotide 3’-phosphodiesterase (CNPase): enzymatic activity but doesn’t appear to have functional significance

Myelin-associated glycoprotein (MAG): cell adhesion factor, myelin-derived axonal growth inhibitor

Oligodendrocyte myelin glycoprotein (OMgp): cell adhesion factor, myelin-derived axonal growth inhibitor

Question 11

Causes of myelin degeneration

Answer 11

Many different factors

Genetic, environmental, viral, autoimmune

Question 12

Leukodystrophies

Answer 12

Genetic disorders of brain white matter

Loss of white matter (myelin) and have multiple underlying genetic causes

Can be specific (temporal-occipital in adreno-leukodystrophy (ALD)) or global (Vanishing white matter disease (VWM))

Diagnosis: metabolites in urine or blood, MRI, neurological testing

Question 13

Regions affected in MS

Answer 13

Multiple foci of myelin loss in spinal cord, optic nerve, cerebellum

Question 14

How might MMP play a role in MS?

Answer 14

Matrix Metalloproteinases (MMP) may attack basal lamina of capillaries and allow entry of B and T cells (which activate astrocytes, macrophages)

Ultimately, nerve axon itself is damaged, leading to neurodegeneration

Question 15

Do we know the mutations involved in leukodystrophies?

Answer 15

Yes, but usually no clear link between specific gene or biochemical pathway affected and the loss of white matter

Question 16

What gene is involved in ALD and how has it been treated?

Answer 16

ABCD1 gene is mutated in ALD, and is a transporter protein that imports very long chain unsaturated fatty acids (VLCF) into the peroxisome to get degraded

In ALD you have accumulation of VLCF because can’t get into peroxisome for degradation

Restoring ABCD1 gene in lentivirus in hematopoietic stem cell gene therapy showed stop of progression of disease up to a year and a half in 2 patients

Question 17

Lorenzo’s oil

Answer 17

Dietary supplement to treat ALD, but very controversial

Lorenzo’s oil contains shorter chain, monounsaturated fatty acids that out-compete biosynthetic machinery so body doesn’t synthesize as much VLCF

Question 18

Potential concequences of reduced myelination

Answer 18

Loss of STDP (spike timing dependent plasticity)

Loss of millisecond precision

Reduced conduction velocity, altered long-range synchronization

Conduction blocks

Abnormal sprouting

Axonal degeneration and secondary inflammation

Reduced transport of presynaptic proteins

Question 19

Adreno-leukodystrophy (ALD)

Answer 19

Massive, regionalized lesions of white matter

X-linked

Mainly early childhood onset

Gene codes for peroxisomal transporter proteion called ADLP coded for by ABCD1 gene (multiple mutations: deletions, point mutations)

Accumulate very long chain fatty acids but unclear how this leads to loss of myelin

Hematopoietic stem cell transplantation has promise for therapy

Lorenzo’s oil made ALD famous

Question 20

Multiple sclerosis (MS)

Answer 20

Loss of white matter in many different regions

Brain stem, cerebellum, optic nerve particularly affected

Varies with geography, especially distance from equator (low from equator up to 40; high from 40-60)

Benign, relapsing-remitting, progressive

Treatment mainly slows progression and relapses, targets immune system and MMP

Question 21

Can axons distal to injury survive?

Answer 21

Axons distal to injury can survive for many days UNLESS they undergo Wallarian Degeneration

Question 22

Can functional regeneration occur in the mature CNS?

Answer 22

No, because glial cells of the mature CNS present many neuronal growth inhibitors which stop th einitial sprouting of the nerve stump

Also, injury attracts reactive astrocytes which form the glial scar and form mechanical barrier which prevents regeneration

Question 23

How is infiltration by reactive astrocytes after injury both good and bad?

Answer 23

Good because limits spread of injury

Bad because scar formation prevents regrowth

Question 24

How might we be able to initiate myelination?

Answer 24

Paper in journal Neuron showed that neuronal activity can (in vitro) initiate myelination by releasing ATP –> ATP acts on astrocytes causing them to release LIG –> LIG promotes myelin production by oligodendrocytes

Question 25

Potential pathways to overcome inhibition of axon growth in the CNS

Answer 25

1) Block inhibitors of axon growth (nogo, MAG, etc)
2) Olfactory ensheathing cells (OEC)
3) Bypass regeneration by plasticity of network

Question 26

Nogo

Answer 26

Protein made by glial cells that prevents axon growth in CNS

Antibodies against Nogo applied to CSF enable regrowth in response to spinal cord injury but controversial whether Nogo-null transgenic animals show increased CNS regeneration

Question 27

Other proteins that inhibit activity for neuronal outgrowth

Answer 27

Myelin associated glycoprotein (MAG)

Oligodendrocyte myelin glycoprotein (OMgp)

Question 28

How do nogo, MAG, OMgp inhibit axon growth?

Answer 28

Bind Nogo-receptor (NgR) on neurons –> NgR interacts with NGF-binding protein p75 and activates neuronal signal transduction cascades through kinases to affect actin cytoskeleton

Possibly signal through neuronal gangliosides

Molecular details of neurite outgrowth inhibition not known yet

Question 29

Olfactory ensheathing cells (OEC)

Answer 29

Olfactory receptor neurons continually generated throughout life of adult animals and are associated with OECs, which are unique population of glial cells with characteristics of both Schwann cells and astrocytes

Located in olfactory epithelium and in olfactory bulb

Ensheath axons of olfactory receptor neurons as they enter bulb and make contact with mitral and periglomerular cells

OECs live at boundary of regeneration-permissive PNS and regeneration-hostile CNS

Cultured OECs shown to ensheath and maybe myelinate axonal processes

Regeneration of CNS shown using OECs in rodents

Question 30

NG2+ oligodendrocyte precursor cells (OPC)

Answer 30

Mixed neuronal/glial cell population that have stem cell potential for forming oligodendrocytes and astrocytes, and they proliferate

Present throughout grey and white matter

Receive synaptic inputs from non-myelinated axons in grey and white matter

Subset of these cells is electrically excitable (can fire APs)

Potential for ongoing myelination in adult and remyelination in demyelinating disease (endogenous or transplanted)

Question 31

Remyelination vs. regeneration

Answer 31

Remyelination via stem cell therapy (OPCs?)

Regeneration by overcoming active block (by Nogo, MAG, OMgp)

Question 32

How do patients with dysfunction of myelination present?

Answer 32

Have both central and peripheral symptoms

Not very specific presentation which is why you need to do MRI

Question 33

Demyelinating diseases

Answer 33

Loss of myelin

Diagnosed mainly by MRI

Many forms with different time courses

Genes, injury, stroke, age, radiation, virus, toxins

MRI shows defined areas of loss (ALD) or multiple demyelination spots (MS)