Myelination And Demyelination Of PNS and MS

Question 1

Oligodendrocyte

Answer 1

Myelin-producing cells of the CNS

Question 2

Oligodendrocyte progenitor cell

Answer 2

Undifferentiated , immature precursor cells, which proliferate and differentiate into mature, myelin-producing oligodendrocytes

Question 3

Dysmyelination

Answer 3

Abnormal to delayed myelin formation resulting from errors in metabolism

Question 4

myelin

Answer 4

Lipid rich layer surrounding nerve cell axons

Question 5

What are the functions of myelin

Answer 5

Protection, metabolic support to neurons
Fast signal conduction (saltatory conduction)

Question 6

Describe leukodystrophies

Answer 6

Grou of rare, cerebral white matter disorders caused by abnormal myelin formation in the brain and spinal cord
Genetic in origin
Leads to dysmelination or demyelination
Symptoms vary by disease, progression and the areas of the brain affected - typically presents with development delays or neurological deterioration, affecting cognitive, language and motor abilities

Question 7

Symptoms of leukodystrophies

Answer 7

Development regression
Poor motor skills
Seizures
Cognitive decline
Symptoms as disease progresses: abnormal Body and muscle tone
Abnormal movements; increased difficulty or loss of ability to walk; trouble with speech; difficulty with eating; decline in vision and/or hearing; decline in mental and physical development

Question 8

Examples of Leukodystrophies

Answer 8

Lysosomal Dysfunction
▪ Krabbe disease.
▪ Metachromatic leukodystrophy (MLD).
Peroxisomal Dysfunction
▪ Adrenoleukodystrophy (ALD).
Myelination Defects
▪ Pelizaeus-Merzbacher disease (PMD).
Astrocyte Defects
▪ Alexander’s disease (AxD)

Question 9

Describe Krabbe Disease

Answer 9

Also known as globoid cell leukodystrophy or galactosylceramide lipidosis.
▪ Autosomal recessive lysosomal storage disorder, affecting 1 in 100,000.
▪ Galactolipids occur in cells that produce myelin, but its accumulation can be
toxic and triggers the destruction of oligodendroglia.
▪ KD results in a lack of galactocerebrosidase (GALC), which is needed for the
breakdown of lysosomal galactolipids.
▪ Increased uptake of galactolipids by microglia also transforms them to
abnormal, toxic cells known as globoid cells.
▪ Globoids promote myelin-damaging inflammation in the CNS and PNS.
▪ Leads to dysmyelination (early onset) or demyelination (late onset).
▪ Treatments: bone marrow and/or umbilical cord stem cell transplants.
▪ Improves development, QOL and life expectancy.

Question 10

Symptoms of Krabbe Disease

Answer 10

Feeding difficulties
Seizures
Developmental delays, regression
Fevers without infection
Irritability
Poor head control
Hypertonic
Deaf/blindness
Walking difficulties (late onset)
Poor hand coordination (late onset)

Question 11

Describe metachromatic leukodystrophy

Answer 11

▪ Autosomal recessive lysosomal storage disorder, affecting 1 in 40,000.
▪ Onset can occur during late infancy (<2 yrs, rapid disease progression),
juvenile (3-16 yrs) or adulthood (16+ yrs, slow disease progression).
▪ MLD is caused by mutations in the ARSA or PSAP (less common) genes.
▪ ARSA encodes for cerebroside-sulfatase, which is needed to breakdown
lipids called sulfatides.
▪ Sulfatides accumulate in MLD and interfere with the production of myelin by
destroying oligodendroglia (CNS) and schwann cells (PNS).
▪ Leads to dysmyelination (infant-juvenile onset) or demyelination (adulthood
onset).
▪ Treatment: Stem cell transplants.

Question 12

Symptoms of MLD

Answer 12

Memory loss
Loss of motor skills
Poor muscle function/paralysis
Loss of bowel and bladder function
Gallbladder problems
Deaf/blindness
Seizures
Emotional and behavioural issues

Question 13

Describe adrenoleukodystrophy

Answer 13

▪ X-linked recessive peroxisomal disorder, affecting 1 in 17,000.
▪ Forms of ALD: Childhood onset (4-10 yrs, rapid disease progression),
Addison’s disease and adrenomyeloneuropathy (slow disease progression).
▪ Affects males more severely than females.
▪ ABCD1 encodes for the adrenoleukodystrophy protein, which is required for
the breakdown of very long-chain fatty acids (VLCFAs).
▪ In ALD, VLCFAs accumulate in the brain and adrenal glands and results in
neuroinflammation.
▪ This inflammatory response damages the myelin sheath and leads to
cerebral demyelination (white matter loss).
▪ Treatments: Stem cell transplants, adrenal insufficiency treatment,
medication or physical therapy.

Question 14

Describe the symptoms of ALD

Answer 14

▪ Learning disabilities
▪ Seizures
▪ Dysphagia (swallowing difficulties)
▪ Deaf/blindness
▪ Poor coordination/balance
▪ Fatigue
▪ Progressive dementia
▪ Muscle weakness
▪ Stiff gait when walking (late onset)
▪ Bladder and bowel dysfunctions (late onset

Question 15

Describe pelizaeus-merzbacher disease (PMD)

Answer 15

▪ X-linked recessive dysmyelinating disease, affecting 1 in 200,000.
▪ Forms of PMD: Classic (common, 1+ yrs) and connatal (more severe, <1 yr).
▪ PMD is caused by mutations in the PLP1 gene, which encodes the proteins
PLP1 and DM20 in the CNS.
▪ PLP1 and DM20 are the main proteins found in myelin.
▪ A lack of PLP1 and DM20 leads to dysmyelination – poor myelin
development (hypomyelination).
▪ Nervous system function impaired.
▪ A different mutation of the PLP1 gene can also lead to spastic paraplegia
type 2 (SP2).
▪ No treatment available.

Question 16

Symptoms of PMD

Answer 16

Hypotonia
Nystagmus
Delayed motor skills
Muscle stiffness
Ataxia
Poor cognitive abilities
Poor cognitive vilifies
Speech difficulties
Feeding difficulties
Joint deformities
Seizures

Question 17

Describe Alexander’s disease AxD

Answer 17

▪ Autosomal dominant disease, affecting 1 in 1,000,000.
▪ Onset can occur during infancy (onset <2 yrs, more severe), juvenile (onset
4-10 yrs) or adulthood (onset 16+ yrs, rarest).
▪ AxD is caused by a mutation in the astrocyte gene GFAP (glial fibrillary acidic
protein).
▪ GFAP is involved in the structural development of cells, providing lipids to
oligodendrocytes during myelin formation.
▪ In AxD, abnormal structures called Rosenthal fibres accumulate within
astrocytes, preventing normal cell functions.
▪ This affects the development and structural integrity of myelin, and leads to
white matter impairments.
▪ No treatment available.

Question 18

Symptoms of AxS

Answer 18

E nlarged brain and head size
▪ Seizures
▪ Stiffness

Developmental delays
▪ Feeding difficulties
▪ Speech abnormalities (juvenile-adult)
▪ Swallowing difficulties (juvenile-adult)
▪ Ataxia (poor balance) (juvenile-adult)
▪ Vomiting (juvenile-adult)
Liss of motor control

Question 19

Consequences of demyelination

Answer 19

Alterations in axonal signalling
Neuronal and axonal loss
Physical abnormalities in function - dependent on area affected

Question 20

Causes of demyelination

Answer 20

Inflammation/immune related
Infections
Hypoxia-ischaemic injury eg stroke
TBI
Metabolic diseases
Toxin induced eg vitamin B12 deficiency, cyanide
Genetics eg MLD

Question 21

What are the mechanisms of demyelination

Answer 21

Immune mediated or autoimmune
Myelin antigens (MOG, MBP, PLP, MAG)
Possible mechanism: molecular mimicry

Question 22

Describe immune mediated demyelination

Answer 22

Immune-mediated demyelination commonly occurs in MS pathology.
It is a pro-inflammatory immune response from both infiltrating and CNS-resident
immune cells.
Cells Involved:
▪ T cells (CD4s and CD8s) (infiltrating/resident)
▪ B cells (infiltrating/resident)
▪ Macrophages (infiltrating)
▪ Microglia (resident)
▪ Reactive astrocytes (resident)

Question 23

Describe demyelination

Answer 23

Naturally occurring process in the CNS
Involves recruitment, proliferation, and differentiation of OPCs into mature myelin-producing oligodendrocytes
Newly formed myelin is thinner

Question 24

Describe the mechanisms involved in demyelination

Answer 24

Removal of myelin debris by microglia
Recruitment and proliferation of OPCs
Differentiation of OPCs into mature oligodendrocytes
Mature oligodendrocytes produce myelin
Myelin wraps around exposed axons

Question 25

Demyelination can also occur in the ..

Answer 25

PNS

Question 26

Exemplars of demyelinating diseases of the PNS

Answer 26

▪ Guillain-Barre syndrome (GBS). ▪ Inflammatory demyelinating polyradiculoneuropathy (CIPD). ▪ Multifocal motor neuropathy (MMN). ▪ Charcot-Marie-Tooth disease (CMT).

Question 27

Describe Guillain-Barré syndrome

Answer 27

Symptoms: ▪ Paresthesia (pins and needles) ▪ Weakness ▪ Ataxia and difficulty walking ▪ Difficulty swallowing and/or breathing ▪ Double vision ▪ Loss of bowel and bladder function ▪ Rapid heart rate ▪ Low or high blood pressure ▪ Affects 1-2 in 100,000. ▪ Forms of GBS: Acute inflammatory demyelinating polyradiculoneuropathy (AIDP), Miller Fisher syndrome (MFS) and Acute motor axonal neuropathy (AMAN). ▪ Cause of GBS is unknown but has been linked to gastrointestinal infections and the Zika virus. ▪ GBS is an autoimmune disease - T cells/B cells/macrophages attack myelin- producing Schwann cells. ▪ Acute demyelination occurs (only in AIDP). ▪ Complete recovery is possible with Schwann cell remyelination. ▪ Treatments: Plasma exchange and immunoglobulin therapy.

Question 28

Describe chronic inflammatory demyelinating polyneuropathy (CIDP)

Answer 28

Symptoms: ▪ Paresthesia (pins and needles) ▪ Gradual weakening of arms and legs ▪ Loss of reflexes ▪ Ataxia and difficulty walking ▪ Fatigue ▪ Affects 5-7 in 100,000. ▪ Immune-mediated pathology is similar to GBS, but the disease is chronic. ▪ No virus or infection found to precede CIPD (cause unknown). ▪ Forms of CIDP: Progressive (continuously worsens), recurrent (on/off symptoms) and monophasic (disease occurs for 1-3 yrs). ▪ Is an autoimmune disease - T cells/B cells/macrophages attack myelin- producing Schwann cells. ▪ Treatment needed to improve condition. ▪ Treatments: Corticosteroids, high-dose intravenous immune globulins (IVIG) or plasma exchange.

Question 29

Describe multi focal motor neuropathy (MMN)

Answer 29

Symptoms: ▪ Weakness ▪ Muscle cramping and twitching ▪ Muscle wasting ▪ Wrist and foot drop ▪ Affects <1 in 100,000. ▪ Cause unknown, thought to result from abnormal immune responses. ▪ Immune-mediated pathology is similar to CIPD, but the disease is considered asymmetric – affecting each side of the body differently. ▪ MMN is also linked to an increase in anti-GM1 antibodies - sensory/motor issues. ▪ Treatments: High-dose intravenous immune globulins (IVIG).

Question 30

Describe Charcot-Marie-Tooth Disease (CMT)

Answer 30

▪ Affects 1 in 2,500. ▪ Hereditary group of disorders affecting both motor and sensory peripheral nerve. ▪ CMT is caused by mutations in ~40 genes. ▪ Peripheral myelin protein 22 (PMP22) (produced by Schwann cells) is the most commonly affected gene. ▪ Function of PMP22 is unknown, but may be needed for Schwann cell growth and differentiation. ▪ CMT involves both dysmyelination and demyelination, with evidence of delayed myelination and myelin breakdown. ▪ Treatments: Physical and occupational therapy, and surgery to correct deformities (No medication currently available). Symptoms: ▪ Weakness ▪ Muscle wasting ▪ High foot arches ▪ Difficulties walking and/or running ▪ Footdrop ▪ Ataxia ▪ Loss of sensation in legs and feet

Question 31

What is the main component of white matter

Answer 31

Myelin

Question 32

Myelin is

Answer 32

A spiral of specialised lipi-rich plasma membrane that is tightly wrapped around the axons

Question 33

myelin functions

Answer 33

• offers protection and insulation to axons • enables rapid and synchronized signal conduction • contributes structural and metabolic support to neurons • plays an important role in plasticity and learning

Question 34

Describe myelination during development

Answer 34

Myelination starts late in development and occurs predominantly postnatal. • Myelination is first detected in subcortical regions at 20-28 weeks of gestation. • Myelin occurs in a caudal to rostral direction: first in the spinal cord and thenin the hindbrain, midbrain and forebrain. • Greatly contributes to brain growth and maturation. • Myelination is largely complete by the end of the 2nd year of life • and progressively continues into young adulthood

Question 35

Myelination pattern correlates with

Answer 35

Progressive neurodevelopment milestones and follows a specific time course and pattern

Question 36

Myelination pattern correlates with increase in vocabulary after 18 months

Answer 36

Coincides with myelination of brain regions related to language

Question 37

What part of the brain isn not completely myelinated until late adolescence

Answer 37

Prefrontal cortex

Question 38

What can cause altered myelination

Answer 38

Prenatal and postnatal exposure to insults such as toxins, hypoxia, malnutrition or alcohol can cause altered myelination in the adult brain

Question 39

Delayed myelination has been associated to

Answer 39

Poor cognitive, neurodevelopmental and neuropsychiatric outcomes

Question 40

Describe myelination in FASD - foetal alcohol spectrum disorder

Answer 40

Delayed myelination, reduced myelin thickness, ultra structural myelin abnormalities Delayed/reduced Oligodendrocyte differentiation and expression of MBP and myelin associated protein Oligodendrocyte apoptosis Abnormalities in biochemical profile of myelin White matter reduction and abnormalities

Question 41

What leads to demyelinating or dysmyelinating diseases

Answer 41

Infectious agents, virus Trauma, physical injuries Insults during development; toxins, alcohol, malnutrition Immune mediated eg MS Genetic physical injuries Metabolic deficiency eg minerals, vitamins

Question 42

Describe glial cells

Answer 42

• are supporting and protecting cells in the CNS and PNS • are not excitable but respond to neuronal activity • are 5-10 times more numerous than neurons • are essential modulators of neuronal function and health: - Guide developing neurons to destination - Buffer ions and metabolic products - Modulate communication between neurons - Immunosurveillence - Myelinating cell

Question 43

Oligodendrocytes can wrap up to…

Answer 43

50 different axons

Question 44

Schwann cells wrap around

Answer 44

A single axon

Question 45

Oligodendrocyte and myelination

Answer 45

1. Oligodendrocyte progenitor cell differentiate from neural stem cells 2. OPC migration and proliferation 3. They recognise their target axon 4. Proliferation inhibited and OPCs differentiate into pre-myelinating oligodendrocytes (OLs) 5. Finally, differentiation into mature OLs with membrane outgrowth and axonal wrapping

Question 46

Describe adult OPCs

Answer 46

A proportion of OPCs remain undifferentiated NDD persist as quiescent cells within the adult CNS They comprise 5-8% of the total cell population and are distributed throughout gray and white matter Under Pathophysiological conditions they are recruited to generate new OLs and myelin sheaths : REmyelination

Question 47

OPCs are generated in ……..

Answer 47

Multiple spatial and temporal waves

Question 48

OPCs and OLs form ……

Answer 48

Heterogenous cell populations with differences in fucntional and differentiation capacities

Question 49

Describe Schwann cells and PNS myelination

Answer 49

• SCs generate from neural crest cells • They develop first to SC precursor and then to immature SC • Immature SCs undergo differentiation to myelinating SC or non-myelinating SC • Differentiation to myelinating SCs is controlled by radial axonal sorting (axons > 1 μm) and Neuregulin-1 type III levels. • SC can generate ~100 layers of its own membrane. • No cytoplasm between the membranes. • NEURILEMMA: thick outermost coil of myelin sheath, which contains nucleus and most of its cytoplasm. • Essential for an injured nerve to regenerate.

Question 50

Thickness of myelination in PNS and CNS

Answer 50

CNS - >0.2um PNS - >1um

Question 51

Myelination is highly correlated to

Answer 51

Diameter of the axon

Question 52

Myelination in CNS is controlled by

Answer 52

Neuronal activity and growth/inhibitory factors

Question 53

Myelination of PNS is controlled by

Answer 53

Threshold levels of NRG1-III in PNS

Question 54

Insulating properties of internodes attributed to

Answer 54

Compact myelin

Question 55

Describe the composition of the myelin sheath

Answer 55

• Ratio 30% protein : 70% lipids • Only small set of proteins reside within the compacted myelin • Structural MBP and PLP proteins are crucial in compaction process • MAG and MOG mediate glial-axonal interaction and junction

Question 56

Internode

Answer 56

Portion of the axon fully insulated by compact myelin between 2 nodes of Ranvier

Question 57

Nodes of Ranvier

Answer 57

Short unmyelinated segment containing listers of voltage gates Na channels

Question 58

Paranodes

Answer 58

Tight junctions between non-compacted myelin loops and the underlining axolemma

Question 59

Juxtaparanodes

Answer 59

Contain voltage gated K channels

Question 60

Describe saltatory conduction in myelinated axons

Answer 60

Insulating/Low capacitance of sheath • APs are generated only in the nodes of Ranvier • Voltage-gated Na+ and K+ channels confined to the nodes of Ranvier and the juxtaparanodal membrane respectively.

Question 61

Increasing axon size =

Answer 61

decreasing the internal resistance

Question 62

myelination =

Answer 62

Decreasing the trans-fibre capacitance of the axon

Question 63

During evolution 2 distinct strategies for achieving increased conduction velocity

Answer 63

Increasing axon size Myelination

Question 64

Myelin provides …….. but at what cost?

Answer 64

Provides nervous system of vertebrates with a crucial fucntional advantage but this advantage may come at a metabolic cost: the myelin sheath isolates myelinated axons from the surrounding environment, a source of tropic and other support factors

Question 65

Describe function of lactate

Answer 65

Lactate to generate metabolic energy in th form of ATP molecules OLs can take or generate lactate and transfer it to the axon Thus metabolic support from OLs may be vital for neuronal and axonal metabolism and integrity Lactate or pyruvate can diffuses through cytoplasmic channels It reaches the peri axonal space via monocarboxylate transporters MCT1 Loss of MCT1 in OLs leads to axonal degeneration

Question 66

Describe adaptive myelination

Answer 66

Myelination is mostly a postnatal process that peaks during childhood Production of new myelin is still possible in adulthood Adults who actively learn complex tasks show increased myelination in specific regions o the brain

Question 67

adaptive myelination and learning

Answer 67

Learning to juggle/ computer games are associated with structural changes in white matter pathways in humans, while learning a motor skill can lead to changes in myelination in rodents

Question 68

Axonal activity and Ca control controls:

Answer 68

Myelin sheath growth Modulates the elongation of individual myelin sheaths during development

Question 69

Conduction velocity…..

Answer 69

Could be modifiable through changes in myelin to optimise the timing of information transmission through neural circuits

Question 70

Myelin does not simply maximise conduction velocity it….

Answer 70

Also provides a substrate for additional control of the timing of inputs during development and in adult neural circuits

Question 71

Former view of OLs as static cell types now….

Answer 71

We understand that OLs establish a crucially important partnership with axons to modulate their metabolic function, and that myelin participates in the remodelling of brain circuitry according to experience