ALS

Question 1

Define ALS

Answer 1

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

Question 2

What are the symptoms?

Answer 2

progressive UMN and LMN
onset- slurred speech, dysphagia, weak grip, foot drop
progression- dysnopea, subtle cognitive impairement, inability to walk/stand/write

Question 3

What pathophysiology underlies ALS?

Answer 3

proteinous inclusions in both motor neurons and astrocytes in human

Question 4

UMN and LMN

Answer 4

UMN- hyperreflexia, hypertonia, extensor plantar response

LMN- hyporeflexia, hypotonia, fasiculations

Question 5

Genes causing ALS?

Answer 5

FUS, TDP43, SOD1, C9orf72- Turner et al 2013

Question 6

What is the most common mutation in both sporadic and familial ALS?

Answer 6

C9orf72

Question 7

Talk about TDP-43

Answer 7

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

Question 8

What does sreedharan et al 2008 say about TDP-43?

Answer 8

mutant forms of TDP-43 fragmented in vitro MORE READILY than wild type causing neural apoptosis and developmental delay in the chick embryo

Question 9

Talk about the SOD1 mutation

Answer 9

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

Question 10

What does the SOD1 knockout mice model show?

Answer 10

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

Question 11

What does the gain of function SOD1 mutation result in?

Answer 11

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

Question 12

differences of the accumulation of TDP-43 in the SOD1 mutations and C90rf72?

Answer 12

SOD1 mutations- no aggregates

C9orf72- the TDP-43 are in different locations

Question 13

Talk about EAAT2

Answer 13

Glial glutamate transporters clear glutamate from synapses in motor neurons and in sporadic ALS glutamate levels are elevated

Question 14

What did rothstein et al 1996 say?

Answer 14

lowering the EAAT2 levels with antisense oligonucleotides induces neuronal death because these receptors are important in maintaining reduced levels of extracellular glutamate

Question 15

What is the role of growth factors in ALS?

Answer 15

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

Question 16

What is the relationship between GLUR2 and ALS?

Answer 16

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

Question 17

Talk about riluzole

Answer 17

extends survival by 2-3 months and only approved drug to treat ALS and acts to decrease motor neurone excitability and limit excitotoxicity

Question 18

How does ceftriaxone work?

Answer 18

cepahlosporin antibiotic that increases the glial mediated glutamate transport by stimulating expression of EAAT2

Question 19

What are the mitochondrial targets of ALS therapeutics?

Answer 19

olesoxime- mitochondrial pore modulator - clinical trails with olesoxime
dexpramipexole- lowers oxidative stress and maintain mitochondrial function

Question 20

What does ACE-031 do?

Answer 20

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

Question 21

Stem cell therapy and ALS

Answer 21

more likely to offer protection

Question 22

CK-2017357 and ALS

Answer 22

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

Question 23

ASO targetted gene silencing of SOD1 mutations - who said that?

Answer 23

Miller