ALS Flashcards
ALS stands for
Amyotrophic Lateral Sclerosis (ALS)
ALS aka
Lou Gehrig’s disease
ALS definition
Rapidly progressive and fatal neurodegenerative disorder of motoneurons
ALS affects
both corticobulbar (upper) and corticospinal (lower) motoneurons
ALS is characterized by
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.)
Death usually occurs within __ of ALS onset
5 years; Progression to death for paralysis of respiratory muscles in 3-5 years
Epidemiology of ALS
1.5:100,000
Average age of ALS onset
52-65 years
Symptoms of ALS: 2 main types
Progressive muscle weakness and Cognitive changes
Cognitive changes in ALS
may be present in up to 50% of ALS cases
executive dysfunction, language and memory impairment
Muscle affects in ALS
Progressive muscle weakness, fasciculations (muscle twitch) , slowness of movement; respiratory dysfunction in advanced stages with terminal respiratory failure
T/F: fasciculations can occur in healthy individuals
TRUE
can be due to stress, mineral deficiencies
Other symptoms in ALS
Fronto-temporal dementia and psychiatric symptoms develop in 15% of ALS patients.
ALS and FTD
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
ALS-Frontotemporal dementia continuum
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
Sporadic ALS accounts for __% of all cases.
90%; There is a strong genetic component in sporadic ALS
Familiar ALS account for __% of cases.
10%
ALS pathogenesis
Most likely a combination of both environmental and genetic factors
contribute to the pathogenesis of sporadic ALS.
Environmental factors that might (conclusive results are missing) predispose to ALS are:
- lead
- aluminum
- exposure to fertilizers and pesticides
- head injuries/ concussions (increased risk of ALS in war veterans and athletes)
Lead vs aluminum in ALS
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
Most commonly mutated genes in ALS
SOD1
TARDBP (TDP-43)
FUS
C9orf72
SOD1 gene–what protein
Cu-Zn superoxide dismutase
TARDBP gene–what protein
TDP-43
ALS genetic: 4 clusters of genes
Involved in:
- cytoskeletal dynamics
- RNA cycling and life cycle
- proteostasic mechanisms and autophagy
- mitochondrial function and oxidative stress
SOD1 gene is involved in
mitochondrial fucntion and oxidative stress
TDP-43 involved in
RNA binding
FUS involved in
RNA binding
C9orf72 involved in
RNA cycling + life factor
In most causes ALS-causing mutations are ____ mutations with the exception of ____
MISSENSE, except C9orf72 which is a massive intro expansion
Genes are their penetrance for either FTD or ALS
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
ALS molecular mechanisms: overview
- 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
Genes involved in cytoskeletal defects and altered axonal transport
Dynactin 1
Profilin 1
Tubulin alpha4A
Genes involved in disturbances in RNA metabolism
FUS* TDP-43* C9ORF72* hnRNPA1 Matrin 3
Genes involved in mitochondrial dysfunction
SOD1*
C9ORF72*
CHCHD10
Genes involved in disturbances in protein quality control
Ubiquilin 2 VCP Optineurin Sequestosome 1 TBK1
Gene involved in hyperactivative microglia
C9ORF72*
___ is the 1st gene associated with familial ALS and __ is most common ALS-causing mutation
SOD1; C9ORF72
SOD 1
- 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
SOD1 protein role
enzyme responsible for toxification of superoxide anions
SOD1 first believed to be _____ BUt is now understood to be due to ____
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
T/F: Markers of oxidative stress are found in all SOD1 caused ALS states
FALSE; only found in some
SOD1 activity is not related to toxicity
SOD1 mutations in ALS result in ____ leading to ….
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
C9ORF72 is unlike other mutations in ALS because
IT is not a missense mutation
It is exanucleotide expansion
what is the mutation in C9ORF72 that causes ALS
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
Proposed mechanism of toxicity of C9orf72: original thought
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
Proposed mechanism of toxicity of C9orf72: new understanding
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
RAN-translation-mediated toxicity
- 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.
RAN Translation occurs in all reading frames, in both directions and results in
the production of ___ possible dipeptide repeat (DPR)-proteins
5
- Glycinealanine (GA)
- glycine-arginine (GR)
- glycine-proline (GP)
- proline-arginine (PR)
- proline-alanine (PA)
The most toxic DPR are
those containing arginine (GR and PR)
What mediates the toxicity of DPR
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
HOW DPRs are toxic–what they cause
- nucleolar dysfunction
- impaired nucleocytoplasmic transport
- altered RNA granule dynamics
- altered intracellular transport
- mitochondrial problems (and the induction of oxidative stress)
- impaired proteasome function
FUS and TDP-43–common roles
Both proteins are ubiquitous and are involved in DNA repair, regulation of
RNA transport, translation, splicing, microRNA biogenesis, formation of
RNA stress granules.
FUS and TDP-43—-proposed mechanism of toxicity
- 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
Mutant TDP-43 effect on mitochondria
Mutant TDP-43 binds to mitochondrial RNA
and disrupt the mitochondrial respiratory
complex 1
RNA granule
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)
Role of astrocytes in ALS
- 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
Microglia in ALS
Decreasing expression of mutant SOD1 specifically in microglia, slows down
disease progression
ie mutant microglia may have a role in ALS pathology
Oligodendrocytes in ALS
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
Motor neuron death in ALS is due to/largely induced by…
non-cell-autonomous mechanisms involving the dysfunction of glia (esp. astrocytes)
T/F there are therapies that block ALS disease progression
FALSE, current therapies only treat symptoms
Treatments:
- physical and speech therapy
- ADs and benzis
- analgesics
riluzole and edaravone
Physical and speech therapy for ALS
Symptoms control through physical and speech therapy, respiratory
exercises.
ADs and Benzos
control depression and anxiety associated with ALS
Analgesic drugs used for…
for the treatment of musculoskeletal pain, and pain related to cramps and spasticity
Only __ FDA approved drugs specific to ALS
TWO
riluzole and edaravone
Riluzole
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.
edaravone
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
Riluzole action
acts to increase EAAT2 levels to increase the uptake of glutamate by astrocytes
prevent excitotoxicity that drives neuronal death in ALS
Edaravone action
Blocks ROS that leads to neuronal death in ALS
Mitochondria are disrupted in excitotoxicity and contribute to the damage caused by producing ROS
Edaravone clinical trial
saw a 33% decrease in rate of progression
ALS tretaments in development–clinical
- Antisense-oligonucleotide (ASO) therapies in clinical trial for SOD1-linked ALS.
- ASO for C9ORF72 in clinical trial.
ALS treatments in development–preclincal
- Development of RAN-translation inhibitors
- Small molecule inhibitors of C9orf72 secondary structures
- Immunotherapies targeting TDP-43 or DPR-proteins
