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PMCOL 412 > ALS > Flashcards

ALS Flashcards

1
Q

ALS stands for

A

Amyotrophic Lateral Sclerosis (ALS)

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2
Q

ALS aka

A

Lou Gehrig’s disease

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3
Q

ALS definition

A

Rapidly progressive and fatal neurodegenerative disorder of motoneurons

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4
Q

ALS affects

A

both corticobulbar (upper) and corticospinal (lower) motoneurons

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5
Q

ALS is characterized by

A 
Characterized by scarring in the
lateral tracts of the spinal cord
(hence the name “lateral
sclerosis”), and deposition of
cytoplasmic protein inclusions
(TDP-43, SOD1, FUS etc.)
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6
Q

Death usually occurs within __ of ALS onset

A

5 years; Progression to death for paralysis of respiratory muscles in 3-5 years

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7
Q

Epidemiology of ALS

A

1.5:100,000

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8
Q

Average age of ALS onset

A

52-65 years

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9
Q

Symptoms of ALS: 2 main types

A

Progressive muscle weakness and Cognitive changes

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10
Q

Cognitive changes in ALS

A

may be present in up to 50% of ALS cases

executive dysfunction, language and memory impairment

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11
Q

Muscle affects in ALS

A

Progressive muscle weakness, fasciculations (muscle twitch) , slowness of movement; respiratory dysfunction in advanced stages with terminal respiratory failure

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12
Q

T/F: fasciculations can occur in healthy individuals

A

TRUE

can be due to stress, mineral deficiencies

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13
Q

Other symptoms in ALS

A

Fronto-temporal dementia and psychiatric symptoms develop in 15% of ALS patients.

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14
Q

ALS and FTD

A

These diseases occur on a continuum known as the ALS-Frontotemporal dementia continuum
With increased motor problems being related to the ALS-heavy end and cognitive/behavioural problems being related to the FTD-hevay end of the spectrum

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15
Q

ALS-Frontotemporal dementia continuum

A

ALS and FTD are considered phenotypic extremes in a spectrum disorder called FTD-motoneuron disease
Can have pure ALS or pure FTD or mixed pathologies

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16
Q

Sporadic ALS accounts for __% of all cases.

A

90%; There is a strong genetic component in sporadic ALS

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17
Q

Familiar ALS account for __% of cases.

A

10%

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18
Q

ALS pathogenesis

A

Most likely a combination of both environmental and genetic factors
contribute to the pathogenesis of sporadic ALS.

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19
Q

Environmental factors that might (conclusive results are missing) predispose to ALS are:

A
  • lead
  • aluminum
  • exposure to fertilizers and pesticides
  • head injuries/ concussions (increased risk of ALS in war veterans and athletes)
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20
Q

Lead vs aluminum in ALS

A

Lead is more studied and found in tissues of ALS–still inconclusive and may only increase risk by 5%
Aluminum–more severe–mice with high aluminum diet develop ALS-like phenotype

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21
Q

Most commonly mutated genes in ALS

A

SOD1
TARDBP (TDP-43)
FUS
C9orf72

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22
Q

SOD1 gene–what protein

A

Cu-Zn superoxide dismutase

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23
Q

TARDBP gene–what protein

A

TDP-43

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24
Q

ALS genetic: 4 clusters of genes

A

Involved in:

  • cytoskeletal dynamics
  • RNA cycling and life cycle
  • proteostasic mechanisms and autophagy
  • mitochondrial function and oxidative stress
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25
Q

SOD1 gene is involved in

A

mitochondrial fucntion and oxidative stress

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26
Q

TDP-43 involved in

A

RNA binding

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27
Q

FUS involved in

A

RNA binding

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28
Q

C9orf72 involved in

A

RNA cycling + life factor

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29
Q

In most causes ALS-causing mutations are ____ mutations with the exception of ____

A

MISSENSE, except C9orf72 which is a massive intro expansion

30
Q

Genes are their penetrance for either FTD or ALS

A

SOD1 has high penetrance for ALS, but not FTD
Tau, GRN, CHMP2B have high penetrance for FTD but not ALS
FUS, TDP43 have high penetrance for both
C9orf72 has medium penetrance for both

31
Q

ALS molecular mechanisms: overview

A
  • disturbances is protein quality control
  • microglial hyperactivation
  • diminished energy supply from a reduction in MCT1 transporter (in oligodendrocyte)
  • Excitatoicity from reduced glut uptake by astrocytes
  • mitochondrial dysfunction in motor neurons
  • disturbances in RNA metabolism
  • cytoskeletal defects and altered axonal transport
32
Q

Genes involved in cytoskeletal defects and altered axonal transport

A

Dynactin 1
Profilin 1
Tubulin alpha4A

33
Q

Genes involved in disturbances in RNA metabolism

A 
FUS*
TDP-43*
C9ORF72*
hnRNPA1
Matrin 3
34
Q

Genes involved in mitochondrial dysfunction

A

SOD1*
C9ORF72*
CHCHD10

35
Q

Genes involved in disturbances in protein quality control

A 
Ubiquilin 2
VCP
Optineurin
Sequestosome 1
TBK1
36
Q

Gene involved in hyperactivative microglia

A

C9ORF72*

37
Q

___ is the 1st gene associated with familial ALS and __ is most common ALS-causing mutation

A

SOD1; C9ORF72

38
Q

SOD 1

A
  • the gene coding for superoxide dismutase (SOD) 1 was the first gene associated to familiar ALS
  • Pathology seems to develop due to a gain of function of the mutant protein, rather than loss of function
39
Q

SOD1 protein role

A

enzyme responsible for toxification of superoxide anions

40
Q

SOD1 first believed to be _____ BUt is now understood to be due to ____

A

First believed that ALS from SOD1 was caused by loss of function of enzyme leading to ox stress
Now know toxicity is not related to levels of SOD1 activity

41
Q

T/F: Markers of oxidative stress are found in all SOD1 caused ALS states

A

FALSE; only found in some

SOD1 activity is not related to toxicity

42
Q

SOD1 mutations in ALS result in ____ leading to ….

A

Abnormal conformations of the protein leading to gain of function including

  • Formation of protein aggregates (leading to aberrant oxidative chemistry)
  • “Scavenging” of molecular chaperons
  • Proteasome inhibition
43
Q

C9ORF72 is unlike other mutations in ALS because

A

IT is not a missense mutation

It is exanucleotide expansion

44
Q

what is the mutation in C9ORF72 that causes ALS

A

Expansion of a hexanucleotide GGGGCC repeat in chromosome 9 open reading frame 72 (C9orf72)
Healthy individuals have fewer than 23 repeats BUT ALS/FTD patients have hundreds of repeats

45
Q

Proposed mechanism of toxicity of C9orf72: original thought

A

originally thought to be loss of fucntion leading to less C9orf72 protein causing abnormal microglia response
BUT has been shown to have minor role in ALS/FTD pathogenesis

46
Q

Proposed mechanism of toxicity of C9orf72: new understanding

A

Complex secondary structure arising from repeats leads to gain of function

1) RNA foci leading to sequestration of RNA-binding proteins (disrupted RNA metabolism)
2) DPR proteins translation leading to impaired nucleocytoplasmic transport

47
Q

RAN-translation-mediated toxicity

A
  • Repeat-associated non-ATG (RAN) translation of poly-dipeptide-repeat proteins (DRPs) from expanded exanucleotides in the three possible reading frames (polyGA, polyGP, PolyGR).
  • RAN translation occurs in the absence of an initiating AUG codon and is
    initiated by certain RNA secondary structures.
48
Q

RAN Translation occurs in all reading frames, in both directions and results in
the production of ___ possible dipeptide repeat (DPR)-proteins

A

5

  • Glycinealanine (GA)
  • glycine-arginine (GR)
  • glycine-proline (GP)
  • proline-arginine (PR)
  • proline-alanine (PA)
49
Q

The most toxic DPR are

A

those containing arginine (GR and PR)

50
Q

What mediates the toxicity of DPR

A

how polar and charged they are because it increases toxic interactions–polyGR, polyPR are highly charged and polar and therefore the most toxic

  • PolyGA is uncharged and moderately toxic
  • Poly GP and PA are uncharged, have no intercations and therefore are non-toxic
51
Q

HOW DPRs are toxic–what they cause

A
  • nucleolar dysfunction
  • impaired nucleocytoplasmic transport
  • altered RNA granule dynamics
  • altered intracellular transport
  • mitochondrial problems (and the induction of oxidative stress)
  • impaired proteasome function
52
Q

FUS and TDP-43–common roles

A

Both proteins are ubiquitous and are involved in DNA repair, regulation of
RNA transport, translation, splicing, microRNA biogenesis, formation of
RNA stress granules.

53
Q

FUS and TDP-43—-proposed mechanism of toxicity

A
  • Both proteins redistribute from the nucleus to the cytoplasm if mutated and form aggregates:
  • Toxicity by gain of function in the cytoplasm
  • Toxicity by loss of function in the nucleus
54
Q

Mutant TDP-43 effect on mitochondria

A

Mutant TDP-43 binds to mitochondrial RNA
and disrupt the mitochondrial respiratory
complex 1

55
Q

RNA granule

A

aka stress granule
contain RNA, act as a RNA reservoir that release RNA for translation when stress is gone (keeps RNAs while translation is halted for when translation begins again)

56
Q

Role of astrocytes in ALS

A
  • Focal transplantation-based astrocyte replacement is neuroprotective in a
    model of motor neuron disease
  • ALS astrocytes induce death of hES cell-derived motoneurons by production
    of pro-inflammatory cytokines and superoxide (ROS)
    AKA if you transplant astrocytes from ALS into healthy peeps = get ALS
    transplant healthy astrocytes into ALS = neuroprotective
57
Q

Microglia in ALS

A

Decreasing expression of mutant SOD1 specifically in microglia, slows down
disease progression
ie mutant microglia may have a role in ALS pathology

58
Q

Oligodendrocytes in ALS

A

Decreased SOD1 expression in oligodendroglia slows down ALS progression more than when SOD1 levels are reduced in neurons
i.e. presence of SOD1 in oligodendrocytes is more problematic than SOD1 in neurons

59
Q

Motor neuron death in ALS is due to/largely induced by…

A

non-cell-autonomous mechanisms involving the dysfunction of glia (esp. astrocytes)

60
Q

T/F there are therapies that block ALS disease progression

A

FALSE, current therapies only treat symptoms

61
Q

Treatments:

A
  • physical and speech therapy
  • ADs and benzis
  • analgesics
    riluzole and edaravone
62
Q

Physical and speech therapy for ALS

A

Symptoms control through physical and speech therapy, respiratory
exercises.

63
Q

ADs and Benzos

A

control depression and anxiety associated with ALS

64
Q

Analgesic drugs used for…

A

for the treatment of musculoskeletal pain, and pain related to cramps and spasticity

65
Q

Only __ FDA approved drugs specific to ALS

A

TWO

riluzole and edaravone

66
Q

Riluzole

A

One of only two FDA-approved drug specific for ALS is riluzole, to limit excitotoxic damage and prolong the survival of patients by 3-6 months.

67
Q

edaravone

A

The second FDA-approved (currently under review by Health Canada) is edaravone, a potent antioxidant with potential neuroprotective effects also in stroke and in PD.
Effects are modest in ALS

68
Q

Riluzole action

A

acts to increase EAAT2 levels to increase the uptake of glutamate by astrocytes
prevent excitotoxicity that drives neuronal death in ALS

69
Q

Edaravone action

A

Blocks ROS that leads to neuronal death in ALS

Mitochondria are disrupted in excitotoxicity and contribute to the damage caused by producing ROS

70
Q

Edaravone clinical trial

A

saw a 33% decrease in rate of progression

71
Q

ALS tretaments in development–clinical

A
  • Antisense-oligonucleotide (ASO) therapies in clinical trial for SOD1-linked ALS.
  • ASO for C9ORF72 in clinical trial.
72
Q

ALS treatments in development–preclincal

A
  • Development of RAN-translation inhibitors
  • Small molecule inhibitors of C9orf72 secondary structures
  • Immunotherapies targeting TDP-43 or DPR-proteins

PMCOL 412 (35 decks)

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