Oligodendrocyte Biology Relevance to Multiple Sclerosis II

Who named myelin?

Virchow (1864)

Where does the word “myelin” come from?

Greek for “marrow”

Almost all axons with which diameter are myelinated (CNS)?

>0.2 μm

What are the features of myelin?

• Rich in lipids

• Low water content

• Segmental structure (150-200 μm)

How does myelin have a high lipid composition (70-75%)?

• 40-45% phospholipid

• 25% cholesterol

• 25% GalCer

• 5% sulfatide

What is the composition of specific myelin proteins in myelin?

• PLP 17%

• MBP 8%

• CNP 1%

• MAG, MOG,….

What is the action potential driven by?

Membrane potential at nodes of Ranvier

Myelin functions

1. Electrical isolation (from other neurons)

2. Efficient and rapid propagation of pulse conduction along the neuronal axons in a saltatory manner

3. Axonal protection (trophic and metabolic support)

What is myelin a stack of?

Multiple double lipid bilayers

MBP (Myelin Basic Protein) function in myelin compaction

Drives the adhesion of the cytoplasmic surfaces of the membrane

PLP function in myelin compaction

Link the exoplasmic (outside) surfaces together

Why does myelin compaction occur?

Squeezes out excess cytoplasm from between the membranes, creating a dense, compact sheath essential for rapid nerve impulse transmission

CNP function in myelin compaction

Prevents myelin compaction

Paranode function

• Seals the myelin sheath to the axon

• Creates a barrier that confines ion channels to the correct locations

Which protein does Caspr and contactin form tight interactions with at the paranodal region?

NF155

CGT (ceramide galactosyltransferase)

Catalyzes the synthesis of galactosylceramide (GalCer) by adding a galactose molecule to ceramide

CST (Cerebroside sulfotransferase)

Catalyzes the synthesis of sulfatide by transferring a sulfate group from PAPS to galactoceramide (GalCer)

What is the precursor of sulfatide?

GalCer

Why is sulfatide important at the paranodal region?

For proper formation and maintenance of the axo-glial junctions at the paranode

Cytoskeletal interactions at paranodal region functions

Anchor and stabilize the Caspr-Contactin adhesion complex at the paranodal junction

Which stage is sulfatide (O4) a marker for

Immature OLG

Which stage is GalCer a marker for

Mature OLG (O1)

Which stage is PLP and MBP a marker for

Mature OLG

How does sulfatide transport from OLG to myelin?

After synthesis in the ER and Golgi apparatus of the OLG, it is primarily transported to the myelin membrane via vesicular trafficking along the OLG's processes.

How does GalCer transport from the OLG to myelin?

After synthesis in the ER, from the ER it is transported to the myelin membrane via non-vesicular transport and vesicular trafficking

How does MBP transport from the OLG to myelin?

mRNA transport, synthesis “on site”

How does PLP transport from the OLG to myelin?

Vesicular transport (transcytosis, switch in membrane microdomains)

Which proteins arrives first at the site of myelin formation?

MBP

What happens if PLP arrives too early?

Premature compaction of OLG membranes, potentially causing cytotoxicity, impaired OLG differentiation, and ultimately demyelination

What regulates myelin biogenesis?

Neurons

Which mechanism initiates MBP synthesis for myelin biogenesis?

Axonal contact (axonal L1-oligodendroglial F3)

Which major myelin protein is transported to the myelin sheath via transcytosis and whose final release is controlled by soluble neuronal factors?

PLP

Remyelination

The process in which entire myelin sheaths are restored to demyelinated axons, reinstating saltatory conduction, and resolving functional deficits

What are the experimental models of remyelination?

• OPC activation

• OPC recruitment

• OPC differentiation

Remyelination features

• Regeneration of myelin

• Shorter segments

• Thinner segments

Why is remyelination important?

1. Functional recovery (nodal organisation: saltatory conduction)

2. Prevent axonal degeneration

• Oligodendrocyte-derived trophic factor

• Inflammation protective

• Metabolic support

Which cells are involved in remyelinating MS lesions?

OPCs

Why is remyelinating MS lesions not efficient?

Dendrites and cell body can also be myelinated

What are the non-disease related factors as to why remyelination fails in MS?

• Age

• Sex

• Genetic background (intrinsic and extrinsic)

What are the disease related factors as to why remyelination fails in MS?

1. 70% differentiation block

2. 30% recruitment block

Why does remyelination in MS fail in terms of differentiation block?

• Intrinsic differences in OPCs (altered - reduced differentiation potential)

• Environmental restriction (molecular and/or cellular origin)

Why does remyelination in MS fail in terms of recruitment block?

• Deficiency of OPCs at lesion sites

• Lack of mitogenic/motogenic/chemoattractant factors (eg PDGF, FGF-2)

What are the features of microglia?

• Clearance of myelin debris

• Pro-OPC differentiation factors

Which model is dietary for toxin-induced demyelination?

Cuprizone

Fibronectin features

• ECM protein

• 220-250 kDa

• Disulfide-linked dimer

• Multiple splice variants

• 2 forms: plasma and cellular

• Embryogenesis and tissue repair

Which model is used to dissolve lipids and therefore dissolve myelin for toxin-induced remyelination?

Lysolecithin

Role of αvβ1

Migration

Role of αvβ3

Proliferation

Role of αvβ5

Differentiation

Role of α6β1

Survival and myelination

Which ECM protein is fibronectin dominant over?

Laminin-2

How does fibronectin prevent formation of myelin membrane?

It perturbs myelin membrane-directed vesicular trafficking (of PLP for eg)

What does fibronectin do in terms of membrane microdomains?

Interferes with correct formation of membrane microdomains like sulfatide and NF155

What results in fibronectin interfering with NF155?

Disruption of paranodal junctions and axon-glia interactions

Therapeutic strategies to promote remyelination

1. Prevent fibronectin aggregation

2. Clear fibronectin aggregates

3. Bypass fibronectin aggregates