MND and MS Flashcards

1
Q

what is the most common form of MND?

A

amyotrophic lateral sclerosis (ALS)

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2
Q

overview of MND

A
  • umbrella term for a number of different conditions
  • disease characterised loss of function in both UMN in the brain and LMN in the spinal cord
  • progression to loss motor neurons themselves
  • progressive and currently incurable
  • ultimately fatal
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3
Q

most common gene mutations in famial NMD?

A

SOD1, TARDBP1, C9ORF72

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4
Q

what is SOD1?

A

super oxide dismutase 1
- power antioxidant that protects cells from superoxide raidcal (O2-) which react with anything in the cell (free radical with single electron)
- SOD1 aggregates in motor neurons in the spinal cord
- superoxide radicals important in mitochondrial electron chain

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5
Q

prevalence rate of familial NMD

A

5-10%

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6
Q

SOD1 explanation

A

protein aggregates of SOD1
if a mutation makes it very likely for SOD1 to aggregate, that is correlated with the severity of MND
(e.g aggregation propensities of SOD1 G93 hotspot mutatnts mirror ALS clinical phenotypes)
loss of control of SOD1 means loss of control of superocide=exitotoxicity
aggregations are TF toxic

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7
Q

TAR-DNA binding protein 43 (TARDBP1)

A

low mol weight mRNA
binding protein in spinal neurons
may regulate mRNA stability, transolcation and local translation
involved in expression of microRNA therefore loss of proteins (e,g can change dendrite structure)
genrealised loss of function in spinal neurons

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8
Q

c9orf72 (chromosome 9 open reading frame 72)

A

found throughout the brain and in pre-synaptic terminals
hexanucleotide repeated (GGGGCC)
protein that allows mRNA to be read in its open reading frame (triplet codons discrete)

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9
Q

what is sporadic MND?

A

idiopathic (nobody knows the cause)
= 90-95% of cases

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10
Q

causes of sporadic MND

A
  1. protein aggregates – SOD1, TRP43 (same as TARDBP1), ubiquitin (no protein tag)
  2. disruption of axonal transport
  3. loss of glial cells – also oligodendrocytes?
  4. excitotoxicity which links to abnormal mitochondria/cell metabolism
  5. loss to white matter tracts in crus cerebri (corticospinal)
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11
Q

microRNA and post transcriptional regulation

A

microRNA=small non-coding RNA sequences
- produced as long hairpin structures and processed to produce short sections of RNA (<30 bases)

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12
Q

what do microRNAs bind to and what does this cause?

A

bind to RISC (RNA-induced silencing complex) which cleaves target mRNA and this leads to down-regulation of
protein expression

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13
Q

TDP-43 (TARDBP1) and microRNA

A

TDP-43 promotes microRNA biogenesis=drosher and dicer complexes
TRP43 knockdown=fewer neurite extensions
TF essential of growth of dendrites

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14
Q

downregulation of microRNA-9 and TDP-43 mutations

A

mutation of TDP-43 reduces synaptic function which is found in FTD/ALS patients

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15
Q

overview of TARDP43

A

loss of TARDP43 function leads to lower levels of many miRNAs
microRNAs are post-transcriptional regulators
loss of TARDP43 function leads to impaired neurite outgrowth
loss of TARDP43 function leads to impaired synaptic function TARDP43 misregulation is also associated with fronto temporal dementia (FTD)

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15
Q

what is FUS (fused in sarcoma) phase separation modulated by?

A

molecular chaperone and methylation (add/remove CH3 grouples like epignetic changes) of arginie cation-pi interactiom

15
Q

FUS phase separation

A

RNA binding protein involved in RNA
transcription, splicing and translation
undergoes phase changes between
dispersed, liquid droplet and hydrogel states which allows FUS to form transient
membrane-free organelles such as
ribonuclearproteins (RNPs)- carries
RNA and protein cargoes to dendrites and axon ternimals to
regulate local RNA and protein

15
Q

mutations of FUS form

A

mutations result in hypomethylation
and the formation of a fibrillary gel
that cannot revert to a droplet leading to impaired translation

16
Q

what does FUS mutate into?

A

gel form similar to beta pleated sheets (like alpha-synuclein and tangles)
therefore aggregations and prevention of translation link to many motor conditions

17
Q

multiple sclerosis (MS) overview

A
  • condition which can affect brain and/or spinal cord
  • wide range of symptoms like problems with vision, arm or leg movement, sensation or balance
  • lifelong condition but can be mild-serious disability
  • possible to treat symptoms but no cure
18
Q

stats about MS

A
  • more than 100,000 people diagnosed in UK and 1 million worldwide
  • commonly diagnosed at 20/30 but can develop at any age
  • 2-3 times more common in women than men
19
Q

cause of MS

A

autoimmune disease whereby immune cell target the myelin sheath surrounding axons
myeline TF becomes inflamed
- leads to damage/scarring
- loss of function
- ultimately atrophy

20
Q

what is myelin produced by in the CNS?

A

oligodendrocytes

21
Q

localisation of demyelination in MS

A

occurs in small regions, often in the paraventricular regions or surrounding blood vessels
TF blood cells can get into brain because of weakened BBB (T cells, B cells and macrophages)

22
Q

inflammatory phase of MS

A

proteins in myelin look
similar to proteins
recognised as ‘foreign’
by T cells
B cells are activated to
produce antibodies
against myelin
macrophages are
induced to phagocytose myelin
sheath

23
Q

degenerative phase of MS

A

T cells, microglia and
astrocytes produces an
excess of L-glutamate
leads to overexcitation
of oligodendrocytes
and/or neurons
induces axonal atrophy
and/or excitotoxic cell
death

24
Q

overall cause of MS

A

de-myelination diseases are the result of auto-immune attack via ‘molecular mimicry’ where a ‘self’ protein looks very much like a
‘foreign’ one