ALS

Question 1

Average age of onset

Answer 1

55

Question 2

Prevalence 5/100,000 per year in Europe

Answer 2

Chio et al., 2013

Question 3

Sporadic %

Answer 3

90

Question 4

Familial %

Answer 4

5-10

Question 5

Sx at onset

Answer 5

weak grip, decreased dexterity, foot drop, leg stiffness, slurred speech, difficulty chewing

Question 6

Sx progressively

Answer 6

unable to hold things/walk/toilet/feed/talk/swallow. Cognitive deficits (subtle; overt dementia rare)

Question 7

Death 3-5 years from onset usually from respiratory failure. However 10% will live 1-+ years from dx

Answer 7

National Institute of Neurological Disorders and Stroke, 2018

Question 8

UMN dysfunction

Answer 8

modest weakness, hypertonia, hyperreflexia, extensor plantar response

Question 9

LMN dysfunction

Answer 9

major weakness, hypotonia, hyporeflexia, fasciculations, muscle wasting

Question 10

Dx?

Answer 10

clinical, neuroimaging to rule out other conditions

Question 11

Familial ALS genes

Answer 11

C9orf72 25%
SOD1 20%
TDP43 5%

Question 12

TDP-43 normally lives in nucleus processing gene transcripts. In ALS accumulates in cytoplasm of MNs

Answer 12

Arai et al., 2006, Neumann et al., 2006

Question 13

accumulation of TDP43 in 95% of MND cases

Answer 13

Arai et al., 2006, Neumann et al., 2006

Question 14

Mutations in TDP43 found in ALS cases

Answer 14

Sreedharan et al., 2008

Question 15

Mutated TDP43 cytoplasmic aggregates caused neuronal apoptosis and developmental delay in chick embryos

Answer 15

Sreedharan et al., 2008

Question 16

transgenic TDP43 Drosophila models

Answer 16

Li et al., 2010

Question 17

TDP43 knock out zebrafish

Answer 17

Schmid et al., 2013

Question 18

SOD1 encodes metalloprotein (Zn/Cu have roles in enzyme’s function) which converts superoxides to h2o2 and o2

Answer 18

Rosen et al., 1993

Question 19

20% familial cases caused by dom mutation in SOD1

Answer 19

Rosen et al., 1993

Question 20

Most common SOD1 mutation

Answer 20

A4V (but >140 have been found in ALS)

Question 21

Reviews various SOD1 animal models

Answer 21

Joyce et al., 2001

Question 22

SOD1 knockout mouse did not cause ALS – GOF mutation???

Answer 22

Reaume et al., 1996

Question 23

Studies have suggested loss of function contributes to SOD1 mutations

Answer 23

Shefner et al., 1999

Question 24

Mutations in SOD1 cause an exposed…

Answer 24

Cu site

Question 25

Exposed Cu site in SOD1 leads to formation of ...

Answer 25

hydroxyl radicals from hydrogen peroxide --> oxidative damage

Question 26

ALS has been attributed to SOD1 misfolding

Answer 26

Jonsson et al., 2004

Question 27

Mutant SOD1 disrupts mitochondrial function

Answer 27

Smith et al., 2017

Question 28

SOD1 aggregates accumulate in mitochondria

Answer 28

Smith et al., 2017

Question 29

Elevated glutamate in how many cases of sporadic ALS

Answer 29

40%

Question 30

elevated glutamate in 40% cases of sporadic ALS

Answer 30

ALS Association 2017

Question 31

First and only approved tx for ALS blocks glutametergic neurotransmission

Answer 31

Doble, 1996

Question 32

SOD1 mutations affect glutamate transporters ....

Answer 32

EAAT2, GLT1 and AMPARs

Question 33

In study lowered EAAT2 levels resulted in neuronal deat in rats

Answer 33

Rothstein et al., 1996

Question 34

Why are MNs particularly susceptible to excitotoxicity?

Answer 34

a) receive a strong glutametergic input | b) express Ca2+ permeable AMPARs

Question 35

Deletion of part of VEGF causes ALS path in mice

Answer 35

Oosthuyse et al., 2001

Question 36

Onset and progression of MND is delayed in mutant SOD1 mice when VEGF is admin

Answer 36

Azzouz et al., 2004

Question 37

Other growth factors eg GDNF have protective effects similar to VEGF and may work synergistically in rats to slow MND progression

Answer 37

Krakora et al., 2013

Question 38

Astrocytes expressing mutant SOD1 secrete factors toxic to MNs

Answer 38

Fritz 2013

Question 39

Hallmark of ALS accumulation of neurofilaments --> common cytoskeletal proteins in MNs and play role in axonal growth --> defective axonal transport plays role in ALS

Answer 39

Julien 1995

Question 40

Lower GluR2 accelerates MN degeneration and shortens lifespan in SOD1 mice - replacement sig increases lifespan

Answer 40

Van Damme et a., 2005

Question 41

Riluzole extends survival by 2-3 months. decreases VGSCs, potentiating calcium dependent K currents --> inhibits glutamate release

Answer 41

Bellingham 2001

Question 42

Ceftriaxone MoA in ALS

Answer 42

Stimulates expression of EAAT2

Question 43

Ceftriaxone prolongs survival in animal models but mixed results in human trials

Answer 43

Cudkowicz et al., 2014

Question 44

HSP stimulator arimoclomol extends life in SOD1 transgenic mice

Answer 44

Kieran et al., 2004

Question 45

HSPs function

Answer 45

Facilitate normal folding and degradation of proteins (abnormalities promote MN degeneration)

Question 46

Creatine improves mitochondrial function but has been disappointing in clinical trials

Answer 46

Shefner et al., 2004

Question 47

Olesoxime delays onset and extends survival in SOD1 mutant mice; did not show much benefit in ALS pts

Answer 47

Lenglet et al., 2014

Question 48

Dexpramipexole extends survival of SOD1 transgenic mice; no difference from placebo in ALS pts

Answer 48

Cudkowicz et al., 2013

Question 49

Human neural progenitor cells were developed to release GDNF in the CNS of SOD1 mutant mice. These cells showed good survival and integration into grey and white matter

Answer 49

Klein et al., 2005

Question 50

ACE-031 MoA

Answer 50

myostatin inhibitor

Question 51

ACE-031 increased muscle mass in mice

Answer 51

Cadena et al., 2010

Question 52

CK2017357 MoA

Answer 52

increases troponin --> increases muscle force

Question 53

CK2017357 increased muscle strength in a model of myasthenia gravis

Answer 53

Russel et al., 2012

Question 54

Gene therapy slows progression and increases survival in SOD1 mutant mice and rats

Answer 54

McCampbell et al., 2018

Question 55

ISIS 333611 silence SOD1 gene; clinical trials underway proved safe in Phase 1 study

Answer 55

Miller et al., 2013