Amyotrophic Lateral Sclerosis Flashcards
ALS general facts
- 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
what are the 2 types of ALS onset?
describe them
what’s different and what similar?
- 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
what’s the primary risk factor for ALS?
age
70-79
gender link to ALS?
not sure but males are more susceptible than females
is ALS sporadic or familial?
is there a difference?
90% are sporadic
10% are familial
- average age of onset for fALS is 10 years earlier than sALS, otherwise the 2 types are indistinguishable
criteria for ALS diagnosis
- evidence of UMN degradation
- evidence of LMN degradation
- evidence of disease progression (spreading)
- all of this must occur while there is no evidence of any other neurodegenerative disease present
what gene seems to account for a large amount of fALS cases and some sALS cases?
C9ORF72
is the cause of ALS monogenic?
no
- it’s caused by a variety of mutations to multiple genes
ALS progression rate for the first few years
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
C9ORF72 gene expansion problems
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
C9ORF72 loss of protein function mechanism
- gene expansion results in decreased transcription and translation of functioning C9ORF72 protein
- not really critical because protein’s function isn’t very important
C9ORF72 toxic gain of RNA function mechanism
- 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
C9ORF72 toxic gain of protein function mechanism
- 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
SOD1 pathogenic mechanisms
just name them
- toxic gain of protein function
- toxic loss of protein function
SOD1 gene toxic gain of function mechanism
- 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
SOD1 gene toxic loss of function mechanism
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
what supporting cells of the NS are affected by ALS
glial cells
astrocytes
oligodendrocytes
glial cells in ALS vs normal
- normally would secrete neurotrophic factors that keep MNs healthy and alive
- in ALS, secrete toxic factors that are inflammatory and damaging to MNs
astrocytes in ALS vs normal
- 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
oligodendrocytes in ALS vs normal
- 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
what are ROS?
reactive oxygen species
- antioxidants try to control oxidative stress they cause
- are activated by excess Ca2+ present in the cell
glutamate excitotoxicity
- 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
mitochondria in ALS vs. healthy
- 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
cell autonomous processes in ALS
do not depend on any other cell type by the evens within the MNs
- toxic loss and gain of functions
non-cell autonomous processes in ALS
- cell types close by affect the health and fitness of MNs
how is damage to LMN characterized?
muscle wasting and weakness
how is damage to UMN characterized?
slow movement, increased muscle tone and hyper-reflexia
are riluzole benefits best seen in spinal or bulbar onset ALS?
best in bulbar-onset ALS
riluzole facts
- the first drug approved for ALS (1990s)
- mechanism not well understood
riluzole efficacy
- 2 studies both found that patients who received the drug had slightly better survival outcome (gave them a few extra months)
potential riluzole mechanisms
- 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
radicava/edaravone facts
- 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
radicava efficacy
- 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
McCrate and Casper 2008 study
- 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!
Deforges 2009 study
- 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
generalizations of exercise efficacy and ALS
- 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
