ALS Flashcards
Define ALS
most common type of MND - progressive and fatal neurodegeneration - gradual and progressive death of MN
40-70 years onset
3 types- sporadic(90%), familial(5-10%), guamian
What are the symptoms?
progressive UMN and LMN
onset- slurred speech, dysphagia, weak grip, foot drop
progression- dysnopea, subtle cognitive impairement, inability to walk/stand/write
What pathophysiology underlies ALS?
proteinous inclusions in both motor neurons and astrocytes in human
UMN and LMN
UMN- hyperreflexia, hypertonia, extensor plantar response
LMN- hyporeflexia, hypotonia, fasiculations
Genes causing ALS?
FUS, TDP43, SOD1, C9orf72- Turner et al 2013
What is the most common mutation in both sporadic and familial ALS?
C9orf72
Talk about TDP-43
normally TDP-43 resides in the nucleus where it gene transcripts but in ALS TDP-43 abberantly accumulates in the cytoplasm of motor neurons where it forms aggregates
Aggregation of TDP-43 is seen in 95% of all MND cases
What does sreedharan et al 2008 say about TDP-43?
mutant forms of TDP-43 fragmented in vitro MORE READILY than wild type causing neural apoptosis and developmental delay in the chick embryo
Talk about the SOD1 mutation
the protein Cu/Zn superoxide dismutase (SOD1) functions as an anti-oxidant and detoxifies nitric oxide and the most common mutation is the alanine-valine substituition of SOD1 (A4V) resulting in aggressive disease form
What does the SOD1 knockout mice model show?
these mice do not develop ALS therefore the mutations must cause SOD1 to gain a toxic property - gain of function mutation
Issues- the pathological cascade plays out over a very short period of time and this is not a proper mirror of human disease
What does the gain of function SOD1 mutation result in?
copper mediated oxidative damage
toxic protein aggregation - misfolded SOD1 protein
disrupts cytochrome C association with inner mitochondrial membrane which interferes with respiration and causes the production of reactive oxygen species
also interferes with axonal transport
differences of the accumulation of TDP-43 in the SOD1 mutations and C90rf72?
SOD1 mutations- no aggregates
C9orf72- the TDP-43 are in different locations
Talk about EAAT2
Glial glutamate transporters clear glutamate from synapses in motor neurons and in sporadic ALS glutamate levels are elevated
What did rothstein et al 1996 say?
lowering the EAAT2 levels with antisense oligonucleotides induces neuronal death because these receptors are important in maintaining reduced levels of extracellular glutamate
What is the role of growth factors in ALS?
retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model- Kaspar et al 2003
VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse model - Assouz et al 2004
What is the relationship between GLUR2 and ALS?
GLUR2 regulates the calcium permeability of AMPARs
In motor neurones there is a LACK of GLUR2 containing AMPAR making the cell more permeable to calcium and thus more suscpetible to excitotoxicity
Talk about riluzole
extends survival by 2-3 months and only approved drug to treat ALS and acts to decrease motor neurone excitability and limit excitotoxicity
How does ceftriaxone work?
cepahlosporin antibiotic that increases the glial mediated glutamate transport by stimulating expression of EAAT2
What are the mitochondrial targets of ALS therapeutics?
olesoxime- mitochondrial pore modulator - clinical trails with olesoxime
dexpramipexole- lowers oxidative stress and maintain mitochondrial function
What does ACE-031 do?
protein that inhibits negative regulators such as myostatin , in animal models ACE-031 promotes lean muscle growth and strength
But muscle related adverse events contributed to the decision to stop that study- campbell et al
Stem cell therapy and ALS
more likely to offer protection
CK-2017357 and ALS
activates fast skeletal muscle troponin complex by increasing sensitivity to calcium which increases muscle force
well tolerated and muscle strength and pulmonary function imporve compared to placebo - russel et al 2012
ASO targetted gene silencing of SOD1 mutations - who said that?
Miller
