Myelination And Demyelination Of PNS and MS Flashcards
Oligodendrocyte
Myelin-producing cells of the CNS
Oligodendrocyte progenitor cell
Undifferentiated , immature precursor cells, which proliferate and differentiate into mature, myelin-producing oligodendrocytes
Dysmyelination
Abnormal to delayed myelin formation resulting from errors in metabolism
myelin
Lipid rich layer surrounding nerve cell axons
What are the functions of myelin
Protection, metabolic support to neurons
Fast signal conduction (saltatory conduction)
Describe leukodystrophies
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
Symptoms of leukodystrophies
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
Examples of Leukodystrophies
Lysosomal Dysfunction
▪ Krabbe disease.
▪ Metachromatic leukodystrophy (MLD).
Peroxisomal Dysfunction
▪ Adrenoleukodystrophy (ALD).
Myelination Defects
▪ Pelizaeus-Merzbacher disease (PMD).
Astrocyte Defects
▪ Alexander’s disease (AxD)
Describe Krabbe Disease
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.
Symptoms of Krabbe Disease
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)
Describe metachromatic leukodystrophy
▪ 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.
Symptoms of MLD
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
Describe adrenoleukodystrophy
▪ 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.
Describe the symptoms of ALD
▪ 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
Describe pelizaeus-merzbacher disease (PMD)
▪ 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.
Symptoms of PMD
Hypotonia
Nystagmus
Delayed motor skills
Muscle stiffness
Ataxia
Poor cognitive abilities
Poor cognitive vilifies
Speech difficulties
Feeding difficulties
Joint deformities
Seizures
Describe Alexander’s disease AxD
▪ 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.
Symptoms of AxS
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
Consequences of demyelination
Alterations in axonal signalling
Neuronal and axonal loss
Physical abnormalities in function - dependent on area affected
Causes of demyelination
Inflammation/immune related
Infections
Hypoxia-ischaemic injury eg stroke
TBI
Metabolic diseases
Toxin induced eg vitamin B12 deficiency, cyanide
Genetics eg MLD
What are the mechanisms of demyelination
Immune mediated or autoimmune
Myelin antigens (MOG, MBP, PLP, MAG)
Possible mechanism: molecular mimicry
Describe immune mediated demyelination
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)
Describe demyelination
Naturally occurring process in the CNS
Involves recruitment, proliferation, and differentiation of OPCs into mature myelin-producing oligodendrocytes
Newly formed myelin is thinner
Describe the mechanisms involved in demyelination
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
Demyelination can also occur in the ..
PNS
Exemplars of demyelinating diseases of the PNS
▪ Guillain-Barre syndrome (GBS).
▪ Inflammatory demyelinating polyradiculoneuropathy (CIPD).
▪ Multifocal motor neuropathy (MMN).
▪ Charcot-Marie-Tooth disease (CMT).
Describe Guillain-Barré syndrome
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.
Describe chronic inflammatory demyelinating polyneuropathy (CIDP)
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.
Describe multi focal motor neuropathy (MMN)
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).
Describe Charcot-Marie-Tooth Disease (CMT)
▪ 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
What is the main component of white matter
Myelin
Myelin is
A spiral of specialised lipi-rich plasma membrane that is tightly wrapped around the axons
myelin functions
• 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
Describe myelination during development
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
Myelination pattern correlates with
Progressive neurodevelopment milestones and follows a specific time course and pattern
Myelination pattern correlates with increase in vocabulary after 18 months
Coincides with myelination of brain regions related to language
What part of the brain isn not completely myelinated until late adolescence
Prefrontal cortex
What can cause altered myelination
Prenatal and postnatal exposure to insults such as toxins, hypoxia, malnutrition or alcohol can cause altered myelination in the adult brain
Delayed myelination has been associated to
Poor cognitive, neurodevelopmental and neuropsychiatric outcomes
Describe myelination in FASD - foetal alcohol spectrum disorder
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
What leads to demyelinating or dysmyelinating diseases
Infectious agents, virus
Trauma, physical injuries
Insults during development; toxins, alcohol, malnutrition
Immune mediated eg MS
Genetic physical injuries
Metabolic deficiency eg minerals, vitamins
Describe glial cells
• 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
Oligodendrocytes can wrap up to…
50 different axons
Schwann cells wrap around
A single axon
Oligodendrocyte and myelination
- Oligodendrocyte progenitor cell differentiate from neural stem cells
- OPC migration and proliferation
- They recognise their target axon
- Proliferation inhibited and OPCs differentiate into pre-myelinating oligodendrocytes (OLs)
- Finally, differentiation into mature OLs with membrane outgrowth and axonal wrapping
Describe adult OPCs
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
OPCs are generated in ……..
Multiple spatial and temporal waves
OPCs and OLs form ……
Heterogenous cell populations with differences in fucntional and differentiation capacities
Describe Schwann cells and PNS myelination
• 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.
Thickness of myelination in PNS and CNS
CNS - >0.2um
PNS - >1um
Myelination is highly correlated to
Diameter of the axon
Myelination in CNS is controlled by
Neuronal activity and growth/inhibitory factors
Myelination of PNS is controlled by
Threshold levels of NRG1-III in PNS
Insulating properties of internodes attributed to
Compact myelin
Describe the composition of the myelin sheath
• 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
Internode
Portion of the axon fully insulated by compact myelin between 2 nodes of Ranvier
Nodes of Ranvier
Short unmyelinated segment containing listers of voltage gates Na channels
Paranodes
Tight junctions between non-compacted myelin loops and the underlining axolemma
Juxtaparanodes
Contain voltage gated K channels
Describe saltatory conduction in myelinated axons
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.
Increasing axon size =
decreasing the internal resistance
myelination =
Decreasing the trans-fibre capacitance of the axon
During evolution 2 distinct strategies for achieving increased conduction velocity
Increasing axon size
Myelination
Myelin provides …….. but at what cost?
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
Describe function of lactate
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
Describe adaptive myelination
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
adaptive myelination and learning
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
Axonal activity and Ca control controls:
Myelin sheath growth
Modulates the elongation of individual myelin sheaths during development
Conduction velocity…..
Could be modifiable through changes in myelin to optimise the timing of information transmission through neural circuits
Myelin does not simply maximise conduction velocity it….
Also provides a substrate for additional control of the timing of inputs during development and in adult neural circuits
Former view of OLs as static cell types now….
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
