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Kin 3Z03 Neuromuscular Plasticity > Amyotrophic Lateral Sclerosis > Flashcards

Amyotrophic Lateral Sclerosis Flashcards

1
Q

ALS general facts

A
  • a life-limiting neurodegenerative disorder due to the loss of both UMNs and LMNs
  • characterized by progressive decline in neuromuscular function, weakness and spasticity
  • involuntary muscles (autonomic NS) not directly affected
  • cellular mechanism are multi-factorial, complex, not well understood
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2
Q

what are the 2 types of ALS onset?
describe them
what’s different and what similar?

A
  • spinal onset ALS - weakness and wasting in limbs at first
  • bulbar onset ALS - affects muscles of the mouth first (chewing, speaking, swallowing)
    similar ages of onset, signs and symptoms
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3
Q

what’s the primary risk factor for ALS?

A

age

70-79

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4
Q

gender link to ALS?

A

not sure but males are more susceptible than females

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5
Q

is ALS sporadic or familial?

is there a difference?

A

90% are sporadic
10% are familial
- average age of onset for fALS is 10 years earlier than sALS, otherwise the 2 types are indistinguishable

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6
Q

criteria for ALS diagnosis

A
  1. evidence of UMN degradation
  2. evidence of LMN degradation
  3. evidence of disease progression (spreading)
    - all of this must occur while there is no evidence of any other neurodegenerative disease present
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7
Q

what gene seems to account for a large amount of fALS cases and some sALS cases?

A

C9ORF72

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8
Q

is the cause of ALS monogenic?

A

no

- it’s caused by a variety of mutations to multiple genes

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9
Q

ALS progression rate for the first few years

A

first 6 months see a 50% decrease in MUs
2nd 6 months see a 50% decrease in MUs
after this, the decline is less dramatic

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10
Q

C9ORF72 gene expansion problems

A

contains a hexanucleotide sequence GGGGCC that when there are >400 repeats, results in ALS (<30 repeats is healthy)

  • loss of function: protein
  • toxic gain of function: protein and RNA
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11
Q

C9ORF72 loss of protein function mechanism

A
  • gene expansion results in decreased transcription and translation of functioning C9ORF72 protein
  • not really critical because protein’s function isn’t very important
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12
Q

C9ORF72 toxic gain of RNA function mechanism

A
  • gene expansion is transcribed bidirectionally so the many repeats bundle up to form a G-quarduplex nuclear foci (an RNA aggregate that’s packed very densely so is very stable)
  • G-quadruplex nuclear foci attracts and sequesters proteins in the cell that are important for transcription, splicing, translation and transport
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13
Q

C9ORF72 toxic gain of protein function mechanism

A
  • transcripts undergo repeat-associated non-ATG tranlation (RAN translation - ie. it starts somewhere else)
  • results in production of insoluble dipeptides which aggregate into clumps in the cytoplasm and clog organelles like the ER, mitochondria,
  • aggregates also sequester and trap other proteins
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14
Q

SOD1 pathogenic mechanisms

just name them

A
  • toxic gain of protein function

- toxic loss of protein function

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15
Q

SOD1 gene toxic gain of function mechanism

A
  • mutant SOD1 protein dimerize and form mini aggregates which clump with other mini aggregates that ultimately results in aggregation of essential cytoplasmic components
  • affects the proteasome (timely protein breakdown), cytoplasmic chaperones (help protein folding), and mitochondria
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16
Q

SOD1 gene toxic loss of function mechanism

A

SOD1’s usual function is as an antioxidant enzyme

  • it’s loss of function (via dimerization with other SOD1 proteins) results in damaging mitochondria by aggregating proteins there
  • results in greater oxidative stress on the cell
17
Q

what supporting cells of the NS are affected by ALS

A

glial cells
astrocytes
oligodendrocytes

18
Q

glial cells in ALS vs normal

A
  • normally would secrete neurotrophic factors that keep MNs healthy and alive
  • in ALS, secrete toxic factors that are inflammatory and damaging to MNs
19
Q

astrocytes in ALS vs normal

A
  • normally assist MNs in SC by removing excess glutamate (a NT used to communicate)
  • in ALS, astrocytes don’t take up glutamate which causes glutamate excitotoxicity so MNs become hyperactive and damaged
20
Q

oligodendrocytes in ALS vs normal

A
  • normally secrete myelin around axons to help AP propagation, also help with feeding MNs so they can generate ATP
  • in ALS, they become dysfunctional and can’t provide fuel for MNs anymore
21
Q

what are ROS?

A

reactive oxygen species

  • antioxidants try to control oxidative stress they cause
  • are activated by excess Ca2+ present in the cell
22
Q

glutamate excitotoxicity

A
  • leads to Ca2+ influx and activation of Ca2+ dependent proteins which degrade other proteins in the cell
  • too much Ca2+ in the cell also activates proteins called caspaces which initiate apoptosis
  • results in massive generation of free radicals and increased oxidative stress because of mitochondrial dysfunction
23
Q

mitochondria in ALS vs. healthy

A
  • in healthy people, would buffer Ca2+ and oxidative stress but too much of either of these damages the mitochondria and it becomes dysfunctional (like in ALS):
  • mito can’t break down fuel, buffer electrons or Ca2+
  • mito ends up producing more ROS which make it lose its calcium buffering capacity and makes it becomes apoptotic
24
Q

cell autonomous processes in ALS

A

do not depend on any other cell type by the evens within the MNs
- toxic loss and gain of functions

25
Q

non-cell autonomous processes in ALS

A
  • cell types close by affect the health and fitness of MNs
26
Q

how is damage to LMN characterized?

A

muscle wasting and weakness

27
Q

how is damage to UMN characterized?

A

slow movement, increased muscle tone and hyper-reflexia

28
Q

are riluzole benefits best seen in spinal or bulbar onset ALS?

A

best in bulbar-onset ALS

29
Q

riluzole facts

A
  • the first drug approved for ALS (1990s)

- mechanism not well understood

30
Q

riluzole efficacy

A
  • 2 studies both found that patients who received the drug had slightly better survival outcome (gave them a few extra months)
31
Q

potential riluzole mechanisms

A
  • drug increase glutamate uptake by astrocytes and presynaptic neurons
  • drug also limits endogenous release of glutamate from presynaptic neurons
    both of these mech. decrease excitotoxicity to decrease Ca2+ influx
  • drug also inhibits persistent Na+ current which helps decrease pathologic repetitive firing of MNs which causes spasticity
32
Q

radicava/edaravone facts

A
  • approved in 2017 for use in ALS
  • initially approved for stroke in Japan
  • thought to be a very powerful antioxidant that affects ROS production but mechanism still unsure
33
Q

radicava efficacy

A
  • in one study, radicava group was found to have a 33% greater score on the ALS functional rating score (higher score=better function) than placebo group
  • in the same study, found that % FVC (measures respiratory function) was preserved with drug treatment compared to placebo group
34
Q

McCrate and Casper 2008 study

A
  • found chronic exercise increases MN survival in SOD1 ALS
  • volitional running increased MN survival by decreasing astrogliosis - ID’s by a decrease in GFAP protein in immunofluorescence (ie better glutamate removal)
  • mice saw greater quality of life
  • also compared exercise to an IGF-1 drug treatment and found that each individually had similar effects on quality and quantity of life. combining the treatment nearly rescued all MNs!
35
Q

Deforges 2009 study

A
  • forced running in this study had the same effect as being sedentary
  • swimming delayed disease onset and extended MN survival because of less astrogliosis and better oligodendrocyte expression in ventral horn
36
Q

generalizations of exercise efficacy and ALS

A
  • there’s evidence for exercise being safe in ALS mice, depending on frequency, intensity, type and duration
  • results for efficacy are equivocal/slightly in favour w/o exacerbating condition

Kin 3Z03 Neuromuscular Plasticity (5 decks)

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