Motor Neuron Disease

Question 1

What are the 4 main types of MND?

Answer 1

Amyotrophic lateral sclerosis (ALS)
Progressive bulbar palsy (PBP)
Progressive muscular atrophy (PMA)
Primary lateral sclerosis (PLS)

Question 2

Which MNs are affected in ALS?

Answer 2

Upper and lower

Question 3

What are the symptoms of ALS?

Answer 3

Paralysis
Limb weakness
Difficulty keeping head upright
Difficulty with speech and swallowing
Breathing problems
Emotional lability

Question 4

Name the 2 licensed drugs for ALS

Answer 4

Riluzole

Edaravone

Question 5

What is riluzole and what is its effect?

Answer 5

Anti-glutamatergic

Slightly increases survival

Question 6

What is edaravone and what is its effect?

Answer 6

Free radical scavenger - decreases oxi stress

Positive trial data with limited patient sample

Question 7

Which other disease do some ALS patients also have?

Answer 7

FTD

Question 8

Which type of MNs are most vulnerable to death in ALS?

Answer 8

MNs under voluntary control

MNs innervating fast twitch muscles

Question 9

Name 4 genes that cause familial ALS

Answer 9

SOD1
TDP-43
FUS
C9orf72

Question 10

What is the role of TDP-43?

Answer 10

RNA binding protein

Question 11

What is the role of FUS?

Answer 11

RNA binding protein

Question 12

What is the role of SOD1?

Answer 12

Superoxide dismutase - converts superoxide to water/hydrogen peroxide

Question 13

What is the overall way in which SOD1 mutation causes ALS?

Answer 13

Toxic gain-of-function

Question 14

What might the SOD1 toxic gain-of-function involve?

Answer 14

Increased superoxide

Axonal transport

Question 15

Where are TDP-43 and FUS normally located?

Answer 15

Nucleus

Question 16

Where are TDP-43 and FUS located in ALS and what is the effect of this?

Answer 16

Cytoplasm

Form cytoplasmic inclusions - depleted from nucleus

Question 17

What are the 2 proposed mechanisms for how mutant TDP-43 and FUS cause ALS?

Answer 17

Nuclear loss-of-function - transcription, splicing

Cytoplasmic gain-of-function - RNA transport

Question 18

What are the 3 proposed mechanisms for how hexanucleotide repeat expanded C9orf72 cause FTD-ALS?

Answer 18

C9orf72 loss-of-function
RNA toxicity - RNA foci formation
Protein toxicity - RAN translation in HRE - forms toxic DPRs - aggregation-prone

Question 19

What is thought to be the way in which mutant C9orf72 causes FTD-ALS?

Answer 19

RNA-mediated toxicity - gain-of-function

C9orf72 haploinsufficiency - loss-of-function

Question 20

What could cause the heterogeneity seen in ALS survival times?

Answer 20

Mutations in ALS-causing/susceptibility genes

Environmental factors

Question 21

Which environmental factors increase ALS risk?

Answer 21

Serious head trauma
Increased exercise
Heavy metal exposure
Low vitamin A diet

Question 22

Mutations in which gene link ALS to poor blood supply and what is the physiological role of this gene?

Answer 22

ANG

Angiogenesis

Question 23

Which pathogenic mechanisms are thought to be involved in ALS?

Answer 23

Protein aggregation
Oxi stress
Axonal transport defects
Mito dysfunction
Glutamate excitotoxicity
RNA processing

Question 24

How might protein aggregates lead to MN death in ALS?

Answer 24

Proteasome blockage
Autophagy overload
Depletion of essential cellular proteins - e.g. chaperones - increases misfolding - forms more aggregates
Toxicity leads to ER stress and axonal transport deficits

Question 25

Which properties of MNs make them susceptible to excitotoxicity?

Answer 25

Low Ca2+ buffering capacity | High number of Ca2+-permeable AMPARs

Question 26

What could be the effect of the deficits in anterograde and retrograde axonal transport seen in ALS model mice?

Answer 26

Key factors not taken to/from muscle

Question 27

What is the evidence for the role of oxidative damage in ALS?

Answer 27

Increased oxidative damage in post-mortem ALS CNS tissue

Question 28

How is mitochondrial function altered in ALS MNs?

Answer 28

Decreased ETC activity Decreased mito membrane potential Altered Ca2+ homeostasis

Question 29

Where does mutant SOD1 localise to in ALS?

Answer 29

Spinal cord mitochondria

Question 30

How might microglia be involved in ALS pathogenesis?

Answer 30

Become overactive when MNs die Release ROS - toxic Damage MNs - does not cause death

Question 31

How are oligodendrocytes affected in SOD1 mutant mice and what is the effect of this?

Answer 31

Degenerate | Decreases support for MNs

Question 32

What is the role of astrocytes in ALS pathogenesis?

Answer 32

Contribute to induction and propagation of MN death

Question 33

What is the physiological role of astrocytes?

Answer 33

Modulate neuronal excitability - prevent excitotoxicity

Question 34

Which patient characteristic prevents stratification in trials, making it more difficult to identify effective treatments?

Answer 34

Progression rate - varies between individuals

Question 35

Name 2 potential ALS treatment types

Answer 35

ASOs | Stem cells

Question 36

How might ASOs be used to treat ALS?

Answer 36

Prevent mutant gene expression - SOD1, C9orf72

Question 37

How might stem cells be used to treat ALS?

Answer 37

Replace glial cells in spinal cord - increase MN support

Question 38

Which mechanisms could future ALS treatments target?

Answer 38

``` Aggregation MN apoptosis Mitochondrial deficits Axonal transport Microglia ```