Oligodendrocyte Biology Relevance to MS I

Multiple Sclerosis

Chronic, progressive, demyelinating disease of the CNS white and grey matter

Which imaging is usually used to diagnose MS?

Magnetic Resonance Imaging (MRI)

What are the functions of myelin?

1. Electrical isolation

2. Saltatory conduction

3. Metabolic support

4. Protection of axons from degeneration

How does myelin provide metabolic support to axons?

By providing metabolites

What happens to (partially) demyelinated axons

Nerve impulse conduction slows or stops completely

Acute Demyelination

Inflammatory, autoimmune disease that attacks and destroys the myelin sheath

Chronic Demyelination

Long-term damage and destruction of the myelin sheath

What is the average age of onset in MS?

Between 20 and 40

What are the symptoms of MS?

Muscular control affected, causing sensory (numbness, tingling, visual disturbance) and motor symptoms (weakness, tremor, difficulty of walking)

What are the different roles in MS if the cause is unkown?

Autoimmunity, apoptosis of oligodendrocytes, neurodegeneration

“Outside-in” model

MS begins with a peripheral autoimmune response that targets myelin in the CNS

“Inside-out” model

Initial damage occurs within the CNS, such as to myelin or axons, which then triggers an outside autoimmune response

What is the pathology involved in relapsing-remitting MS (RRMS)?

1. Demyelination

2. Inflammation

3. Remyelination

4. “Disturbed” BBB

5. Adaptive immunity

What is the pathology involved in primary and secondary progressive MS?

1. Demyelination

2. Neurodegeneration

3. Hardly remyelination

4. “Closed” BBB

5. Innate immunity, aging

How many genes found by GWAS influence MS?

Approx. 230 genes, mostly related to inflammation

What are the risk factors of MS?

1. Vit. D3 deficiency

2. EBV

3. Smoking

Proteolipid Protein (PLP)

Major structural myelin protein

At which area is HLA found at in mixed active/inactive lesions

At the rim

What type of astrocytes are found in active lesions?

Fibrous astrocytes

What type of astrocytes are found in inactive lesions?

Hypertrophic astrocytes

What type of astrocytes are found in mixed active/inactive lesions?

Scar astrocytes

Which MS has a higher proportion of active lesions?

RRMS

Which MS has mainly inactive lesions and has a higher proportion of mixed active/inactive lesions, and are more severe?

Progressive MS

What can the activity of lesions predict?

The course of MS

Name a type of therapy for MS?

Immune modulation or immune suppression (only for RRMS)

What do therapies do for MS?

Reduces not only the number of relapses, but also the severity

What are the histological hallmarks of MS?

1. Multifocal lesions with demyelination

2. Oligodendrocyte death

3. Microglia activation

4. Astrogliosis

5. Accumulation of blood-borne immune cells

6. Axon loss

What are the different types of heterogeneity in MS?

1. Clinical

2. Lesion

3. Pathology

How is there lesion heterogeneity?

Different cellular composition

What is the role of microtubules and motor proteins (kinesin and dynein) in cytoskeletal transport?

Mediate directional trafficking of myelin vesicles

What is the role of lipid transport?

via vesicular carriers and local lipid synthesis at the myelin sheath

What type of cells are oligodendrocytes (OLGs)?

Glial cells of CNS

What do OLGs produce?

The lipid-rich insulating myelin sheaths which wrap in double phospholipid bilayers around axons

How many axons can OLGs myelinate at the same time?

Up to 70

Which model is correct for myelination

Yo-yo model

What happens during the initiation of myelination (approx. 5 hours)?

• Sheath formation

• Sheath retractions

• Retraction of exploratory processes

What happens during the maturation of myelinating OLG (1-2 days)?

• Sheath retractions

• Stable sheath number

What is the lineage marker for all stages of OLG development?

Olig2

What are the “steps” of OLG development?

1. Early oligodendrocyte progenitor (OPC)

2. Late oligodendrocyte progenitor (OPC)

3. Immature oligodendrocyte (OLG)

4. Mature (myelinating) oligodendrocyte (OLG)

What are the markers for early oligodendrocyte progenitor (OPC)?

NG2, Nkx2.2 (Migratory, proliferative)

What are the markers for late oligodendrocyte progenitor (OPC)?

Sulfatide (O4, surface) (Begins lineage commitment)

What are the markers for immature oligodendrocyte (OLG)?

GalCer (O1, surface), CNP (starts extending process)

What are the markers for mature (myelinating) oligodendrocyte (OLG)?

MAG, MBP, PLP, MOG (forms compact myelin)

Why do around 50% OLGs undergo apoptosis during development?

Due to failed signaling or lack of axonal interaction (“interaction failure”)

How far are soluble signals?

Long distance

How far are contact-mediated signals?

Short distance

Egs of neurotransmitters

Glutamate, ATP

Neurotransmitters function

Activity-dependent myelination

Egs of chemotactic factors

CXCLs, neureglins

Chemotactic factors function

Guide OPC migration

Electrical activity function

Neuronal firing promotes OLG differentiation

PDGF role

Promote proliferation

FGF-2 role

Survival/differentiation

Which receptors does FGF-2 bind to?

FGFR1 and FGFR3 on OLGs

FGFR1

Proliferation

FGFR3

Differentiation

Membrane (lipid) rafts

Small (10-200 nm), heterogenous, highly dynamic, sterol- (cholesterol) and glycosphingolipid-enriched domains that compartmentalise cellular processes

Which processes are the proteins from membrane rafts involved in?

Signal transduction and myelin transport

Which receptor does PDGF bind to?

PDGFαR on OPCs

What is the difference between proliferation and survival in terms of PDGFαR

Where PDGFαR is located in which domain

Which neuronal cell secretes galectin-4 during development

Axons

Galectin-4

Soluble, negative neuronal regulator of myelination (prevents premature wrapping)

Notch-jagged (notch-F3) function

Inhibits premature OLG differentiation

F3-L1 function

Neuron-OLG adhesion and communication

MAG-ganglioside GT1b

Supports survival and myelin wrapping

Integrin α6β1-laminin-2 function

Associated with proliferation and migration

Integrins

Cell surface proteins that connect the inside of a cell to its extended environment by binding to the ECM or other cells, acting as both physical anchors and communication hubs

αvβ1 and αvβ5

Localise within lipid rafts and interact functionally with PDGFαR

What is the amount of PDGF required in absence of integrins?

High

What is the amount of PDGF required in the presence of integrins?

Low

What does microdomain integration ensure?

Asynchronous, spatially restricted signaling for proper myelination timing

Which glycoprotein is expressed by astrocytes?

Fibronectin

Which glycoprotein is expressed by Schwann cells?

Laminin-2

Which oligodendrocyte is fibronectin associated with?

Oligodendrocyte progenitor

Which oligodendrocyte is laminin-2 associated with?

Immature oligodendrocyte