Flashcards in Disorders of CNS myelin Deck (79):
What gives white matter its colour?
What does white matter contain?
What gives white mater its insulative properties?
Where is myelin present?
Central and peripheral nervous systems?
How is CNS myelin formed?
What does each CNS myelin cell form?
With a few exceptions, each cell forms myelinated internodes
What is CNS myelin's major structural protein?
How is PNS myelin formed?
By Schwann cells
What does each PNS myelin cell form?
A single myelinated internode
What is PNS myelin's major structural protein?
What is saltuatory conduction?
'Jumping' between nodes of ranvier i.e. conduction between nodes
What does each oligodedrocyte have?
Several processes each of which maintains a myelin sheath often on different axons
What do Schwann cells form?
A single myelin sheath
What does the cytoplasm filled space allow?
What is a paranode?
Next to node of ranvier, where myelin sheath is anchored to the axon
What is a juxtaparanode?
In between internode and paranode
What does the myelinated CNS axon contain?
Microtubules, neurofilament and actin
What does the non-compact myelin contain?
Microtubules and actin
What does myelin sheath thickness correlate with?
What is G-ratio?
Axon diameter/fibre diameter
What is the G-ratio approx in humans?
What does a single oligodendrocyte produce?
5,000- 50,000 microns2 of myelin membrane surface area/day during development (Pfeiffer et al, 1993)
What is the approx length of a single oligodendrocyte?
What happens to myelin composition in the absence of cholestrol?
Can not be made
What is the composition of myelin?
What are the two major structural proteins in CNS myelin?
Myelin basic protein (MBP, approx 20%)
Proteolipid protein (PLP, approx 50%)
What is the diameter of myelinated axons?
What is the diameter of unmyelinated axons?
What does increasing diameter do for conduction?
Increases conduction velocity
How does myelin accelerate conduction velocity?
Because sodium channels only at nodes at very high density
What is conduction speed for unmyelinated axons?
What is conduction speed for myelinated axons?
What is myelin?
An electrical insulator sheath wrapped around axons
What are the short gaps in myelin alongs axons?
Nodes of Ranvier
What is the function of Nodes of Ranvier?
Increases speed of action potential propagation
What are the main disorders of CNS myelin?
What is Multiple Sclerosis?
Chronic inflammatory demyelinating disease
>100,000 patients in UK (1/500 of the Scottish population)
What is Stroke?
Due to clock in blood flow to the CNS
Oligodendrocytes highly susceptible to ischemia (lack of O2)
Incidence per 100,000/year: Men 202, Women 160
Approx. 20% fatal, >1 million survivors in UK
What is genetic leukodystrophies?
Primary genetic lesion affecting myelin or myelinating cells (e.g. PLP in Pelizaeus Merzbacher disease)
Progressive clinical course
Rare approximately 2/100,000 births for all forms
What are examples of mutations in myelin genes that lead to neurological disorders?
Pelizaeus Mercbacher disease (PMD) and spastic paraplegia type 2
What are the genetic orders in myelin genes due to?
Mutations in proteolipid proteins (PLP1) gene
What is expressed in oligodendrocytes that lead to genetic disorders?
PLP and its smaller isoform DM20 expressed in olgiodendocytes
>100 mutations, identified in the X-linked PLP1 gene
What is PMD?
A prototypic leukodystrophy characterised by a widespread hypomyelination of the CNS
What are the symptoms of PMD?
Impaired motor development, mystagmus (abnormal movements), ataxia, choreoathetosis (abnormal movements of the upper limbs), cognitive impairment
What are the mouse models of PMD?
Spontaneously occuring mutations in mice and rats e.g. rumpshaker and jimpy, mice and the myelin deficient rat
Transgenic animals e.g. PLP1 gene knockout mice, PLP1 overexpressing mice and rats
What causes CNS hypomyelination in mice?
Point mutation in PLP1 gene
What is adrenoleukodystrophy (X-ALD)?
Caused by mutations in the X-linked gene (not known as) adenosine triphosphate binding cassette transporter (ABCD1) gene
What does X-ALD code for?
A peroxisomal membrane protein (ALDP)
What are peroziomes?
Ubiquitous organelles that detoxify reactive oxygen species, B-oxidation of long fatty acids, synthesise plasmalogens
Who does X-ALD affect?
Approx. 1:20,000 males (X linked recessive)
What happens in X-ALD?
Perivascular accumulation of lymphocytes and plasma cells in the CNS
Accumulation of very long chain fatty acids in adrenal cortical cells and microglial
Markedly shortened lifespan
Wha is used to treat ALD?
What was done by Cartier et al (2009) to treat ALD?
Transduced haematopoietic stem cells of two patients with a lentivirus encoding for a functional ABCD1 and transplanted back into the patients
Low levels of ABCD1-expression in peripheral blood cells (only 15% of leukocytes produced ABCD1)
Progressive cerebral demyelination stopped in both patients and the levels of very long chain fatty acids in the plasma as indicators for disease activity decreased
What is used in gene therapy for treating X-ALD?
Haematopoietic stem cell gene therapy with a lentiviral vector
What is M.S,?
Inflammatory demyelinating disease of the CNS- considered to have an autoimmune aetiology?
What is the lifetime risk for northern European Caucasians of getting MS?
1 in 400
What is the most common cause of neurological disability in young adults?
How many people does MS affect in the UK?
What is the prevalence of MS in Scotland?
>200 per 100,000
Who's more likely to get MS?
What does MS cause?
What is the cause of MS?
What is demyelination associated with?
An invasion of T cells and macrophages (inflammation)
What do T cells do?
Normally detect bacterial or viral infections
What do macrophages do?
"Called up" to kill bacteria or infected cells
What has been used to block inflamamtion and cure MS?
What did steroids do as MS treatment?
Used for acute relapses
What did Interferon-B do as MS treatment?
30% reduction in acute disease activity
What did Natalizumab do as MS treatment?
60% reduction in acute disease activity
What did FTY720 do as MS treatment?
60% reduction in acute disease actitvity
What were the problems with these substances used to block inflammation in MS?
Many non responders
Far less effective in progressive MS
No effect on accumulation of disability
What causes axonal damage?
Soluble inflammatory products
Cytotoxic CD8 T cells
What are some examples of soluble inflammatory products?
Nitric oxide, lipases, proteases, cytokines
What causes demyelination?
Exarcebrates effects of NO
Disrupts trophic support
Aberrant ion channel expression
Exposure of "neo-antigenic targets"
What does myelin provide?
Metabolic support for axons
What does NO mediate?
Acute conduction block
What is NO associated with?
How can effects of NO be exacerbated?
High frequency transmission