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Flashcards in Motor neurones disease Deck (53):
1

What is spinal muscular atrophy ?

loss of lower motor neurones in SC and brainstem

2

What are the symptoms of spinal muscular atrophy ?

muscle weakness
atrophy and premature death

3

What is the underlying genetic cause of spinal muscular atrophy ?

due to deletion/mutation of SMN1 gene

4

How is the clinical severity of spinal muscular atrophy determined?

by the copy number of SMN2 gene

5

What is the SMN protein essential for ?

essential for axonal and dendritic development and maintenance of motor neurones
- leading genetic cause of infant mortality

6

What are the features of ALS?

degeneration of both upper and lower motor neurones
muscle weakness
loss of voluntary movement- eye, bladder and bowel movement normally maintained
maintain cognitive function
death often occurs after few years due to respiratory failure
- very selective loss of motor neurones, UMN= corticospinal neurones and LMN= within ventral horn - not the same amount of loss in every individual

7

How do patients with ALS often end up communicating ?

by the use of their eyes

8

What happens to sympathetic activity in ALS patients and why is this thought to occur?

activity is increase but the IML neurones are decreased
- causes a loss of autonomic function
- thought it could be due to change in baroreceptive activity

9

How did they record the sympathetic activity?

insert electrodes into sympathetic nerves in the leg region to carry out recordings
- there is a decline in sympathetic neurones in both T2 and T9 of ALS patients

10

What is the incidence of ALS?

1-2/100,000 people- people dont survive long (3-5 years)

11

What is the prevalence of ALS?

4-6/100,000 people

12

What is the average age of onset?

about 55 years old

13

Which gender is more susceptible to ALS and is it hereditary?

men
- only 10% of cases are familial, the rest are sporadic
this makes it difficult to study

14

What is a key common mutation in familial ALS?

mutations in SOD1 gene account for 20% therefore only 2% of all cases

15

What is another mutation that occurs in ALS?

mutations in the TARDP gene encoding a DNA binding protein TDP-43

16

What can increase risk of ALS?

high levels of activity

17

What are the cascade of events leading to neuronal death ?

SOD1= altered axonal transport therefore stopping transport of proteins, enzymes for neurotransmitters and neuropeptides which are critical
- increased calcium leading to activation of apoptotic pathways to cause cell death
increase in glutamate leads to excitotoxicity

18

How can astrocytes contribute to motoneurone death ?

astrocytes can express mutant SOD1 and when this was tested with cultured motoneurones it caused motoneurons death
- only caused death of motoneurones not GABAergic neurones

19

What is the onset and death rate in animal models of ALS?

onset is about 90 days and death is at about 120 days

20

What does the C83G mutation that is present in human demonstrate in animal models ?

it can separate central and peripheral effects
changes in weight and grip test are shown in homozygote animals with reductions in both weight and grip

21

What are the issues with TDP-43 animal models?

not actually mimicking the effects of ALS
not mimicking muscle weakness
therefore we need more appropriate models to model ALS

22

What is a potentially new model that could be used in ALS?

zebrafish model- can see through the young so you can determine if they are developing properly

23

What neurones are affected in ALS?

not all motonuerones are affected to the same degree
- oculomotor neurones and those in the onuf's nucleus are less susceptible to damage than ventral horn neurones

- facial nucleus is affected- neurones are reduced and those that are present are unhealthy

24

What might correlate with the degree of suscpetiblity of moto neurones to death ?

may correlate with the expression of GluR2
- glutamate receptors lacking the GluR2 subunit are more permeable to calcium therefore an increase in glutamate is crucial
- because abberant editing of the subunit may also increase calcium permeability and cause cell death
- editing efficiency of GluR2 subunit is compromised

25

What was seen in purkinje cells from controls and ALS patients?

looked at % of editing of GluR2 subunit
- the editing efficiency isn't generally affected

26

What transporter is reduced in ALS?

the EAAT2 glial glutamate transporter protein
- this transporter mops up excess glutamate to remove it and prevent is causing excitotoxicity

27

What is interesting about EAAT2 expression and the neurones lost in ALS?

the neurones that are less susceptible to damage have lower EAAT2 in control situation and therefore may normally have lower glutamatergic innervation which may help to protect them

28

What is the expression of EAAT2 like in SOD1 mutant mice ?

EAAT2 in VH of SOD1 mutant mice are not significantly different from controls - species differences
SOD1 mutant mice= not good model - vary in patients

29

What other factor may the degree of susceptibility correlate with ?

correlate with the presence of calcium buffering proteins
- from post mortem examinations of ALS patients, the pyramidal cells in the motor cortex have low levels of calbindin while those in the sensory cortex have higher levels - these reductions in calcium binding proteins are seen in presympatomatic transgenic mice

30

What is calbindin?

it is a calcium buffer= brown reaction product
- VH motoneurones dont have calbindin

31

What is the mechanism behind excitotoxic neuronal death ?

increased glutamate is due to change in AMPAR and there is no buffer

32

What is the current treatment for ALS and is it effective?

riluzole
from italian patients it demonstrated limited success
in another study 58% of patients in placebo were still alive whereas 74% in riluzole group were still alive
high doses of vitamin e with riluzole dont seem to significantly improve the situation

33

What is needed for ALS treatment?

disease modifying drugs not just ones that relieve symptoms

34

Why might calcium buffering proteins being introduced into motoneurones be beneficial ?

it could reduce the excitotoxic response
- parvalbumin immunoreactivoty in VH of control and PV overexpressing mice were compared- cross breeding SOD1 mutant mice with parvalbumin over-expressing mice the number of motoneurons surviving increase while onset of disease and death were delayed

35

Why is blocking calcium channels not always effective?

parvalbumin to motoenurones
- mutant SOD1 motoneurone inclusion were reduced with voltage gated calcium channel blocker, lomerizine
- but in TDP-43 mutants there was no change in the amount of inclusions

36

What could dictate the efficacy of drugs ?

differing underlyng mechanism in the familial forms

37

What effect does lomerizine have on mutant SOD1?

- strong mitochondrial phenotype
- increased mitochondrial and cytosolic calcium concentration
- formation of cytoplasmic inclusions and motor neuron death which can be blocked by lomerizine

38

Is lomerizine effective against mutant FUS or TDP-43?

this form has a milder mitochondrial phenotype
normal mitochondiral and cytosolic calcium
accuulation in the cytoplasm and formation of inclusion leading to disrupted RNA metabolism that cant be blocked by lomerizine

39

What have clinical trials using BDNF shown?

shown that BDNF given intrathecally can be tolerated but over the last 10 years in which ALS patients have been injected with neurotrophic factors there have been no improvements

40

What can GDNF do ?

it may protect facial motoneurons but not VH motoenurones

41

What happened when GDNF or BDNF are injected into muscles of mice?

taken up into VH motoneurons and it led to increased survival time indicating that neurotrophic factors could be beneficial

42

What happens to heat shock proteins ?

they are unregulated in patients with ALS and in SOD1 mutant mice

43

What do heat shock proteins normally act as?

act as cytoprotectants

44

What might the heat shock proteins do in ALS?

they may be unable to counteract the chronic stressful environment so enhancing them may help to alleviate symptoms
- in clincal trials there was no significant benefit

45

What is antimoclomol and what effect did it have ?

it is a drug acting ro increase heat shock response
- treated SOD1 mutant mice with it
-improved movement and muscles
- but giving a drug before symptomatic effects have occurred is not beneficial for mimicking ALS in patients however when they gave the drug 33 days after the survival is just as good indicating the drug is effective !

46

What is different in the EU compared to US about drug licensing ?

in the eu there are special regulatory mechanism that allow marketing of unlicensed drug fulfilling certain criteria:
- meet a significant unmet medical need (preferably life threatening or significantly disabling)

47

What is coyote trying to achieve?

trying to pursue a dual track clinical development of CP-102 for ALS in the EU and then in the US
- Evidence for product safety
- evidence supporting product efficacy is the proposed indication
they have started regulatory approval processes in the eu with the goal of commencing an open label trial of 20 ALS patients in Q3 in 2014. following completion of the trial, coyote would start generally distributing CP-102 to ALS patients in EU under the named patient program

48

What is CP-102(CNS-102 for ALS)?

it is an orally bioavailable small molecule inducer of heat shock protein gene expression

49

What did CP-102 do in pre-clinical animal trials ?

in pre-clinical animal models of neurodegenerative disease it significantly improve animals behaviours and protected neurones from damage compared to controls
it was proven safe and well tolerated in these preliminary trials

50

What was the trial using dexprampexole?

it is a mitochondrial modulator
- 300mg dose was much much better for survival
-101 in trial, 18 withdrew and 12 patients died during the 40 weeks
- 3 died before receiving drug at 16 weeks in
- 7 of the 48 on 50mg doses died while only 2 of the 44 on 300mg dose died
- improved survival and motor function

51

Why are clinical trials for ALS so difficult to do ?

they are difficult to carry out because the patients already have such short life expectancies

52

What did coenzyme 10 do ?

it combats oxidative stress, however it was not useful in people with ALS, even at high doses

53

Why are mitochondrial modulators not that effective?

they have no effect on top-43 or sod1 model and they may not be useful in familial forms