Motor neuron disease 1

Question 1

neurodegenerative disease

Answer 1

disease that selectively kills neurons and progresses over time

Question 2

ALS - full name

Answer 2

amyotrophic lateral sclerosis

sometimes referred to as Lou gehrigs

Question 3

ALS - how does it work

Answer 3

• motor neurons degenration
• reduced signals to musces
• NMJ disrupted
• muscle wasting and weakness
• progressive paralysis

Question 4

ALS after onset

Answer 4

• fatal within 2-5 years of symptomatic onset
• limited treatment options / no cure

Question 5

clinical symptoms of ALS in the limbs/spine (corticospino tract)

Answer 5

• muscle stiffness /spasticity and cramps
• muscle twitching
• weakness in arms, legs, hands, feet
• poor grip strentch

(spreading of muscle weakness inward)

Question 6

clinical symptoms of ALS in bulbar (corticobasal tract)

Answer 6

• degeneration of corticobulbar tract
• weakness
• difficulty swallowing
• pooling of saliva
• spasm of vocal cords
• slow or slurred speech

(spreading of muscle weakness outward)

Question 7

cognitive symptoms of ALS

Answer 7

• episodic memory impairments
• atrophy of frontal and temporal lobes
• personality changes/ language disorder

Question 8

what kind of dementia do ALS patients tend to be diagnoses with and whats the rate

Answer 8

• 15% develop frontotemporal dementia (FTD)

Question 9

genetics of ALS

Answer 9

• 5-10% ALS hereditary - FALS (remainder is sporadic - SALS)
• heterogeneous disease
• some mutations cause both ALS and FTD

Question 10

ALS key mutations

Answer 10

• SOD1
• C9orf72
• TARDBP

Question 11

SOD1 mutations in ALS

Answer 11

• first mutation discovered
• 10-20% familial cases, 1-2% sporadic
• copper-zinc superdioxide dismutase 1
• mostly single aa substitutions

Question 12

what is SOD1

Answer 12

• antioxidant enzyme that breaks down superoxide radicals

Question 13

where is SOD1 found

Answer 13

cytosol, mitochondira, nucleus, ER

Question 14

what is another name for single aa substitutions

Answer 14

missense mutations

Question 15

new treatment for ALS relating to SOD1 mutations

Answer 15

new antisense oligomer (ASO) treatment
- Tofersen
- prevents it being expressed

Question 16

C9orf72 mutations and ALS

Answer 16

• most common cause of ALS
• also causes FTD
• large hexanucleotide repeat expansion (excess sequences in gene)

Question 17

how does the C90rf72 mutation cause genes to die

Answer 17

• in intron 1 or promoter region (non-coding)
• expansion gets transcribed
• expansion translated to produce 5 repetitive dipeptides (DPRs)
• not meant to exist in human brain and become toxic

Question 18

TARDBP what is it

Answer 18

• encodes for TDP-43 (transactive response DNA-binding protein 43) (and RNA-binding protein)

Question 19

what is the role of TARDBP

Answer 19

• DNA repair and RNA processing: regulates transcription, translation, splicing
• primarily nuclear

Question 20

TARDBP in ALS

Answer 20

• > 40 mutations linked to ALS
• rare ~1-3% of all ALS
• also linked to FTD

Question 21

neurodegeneration in ALS motor cortex

Answer 21

• stains show far less/ little cell bodies of motor neurons

Question 22

protein aggregation in neurodegeneration

Answer 22

• insoluble intraneuronal protein aggregates/inclusions in all neurodegenerative disease
• different proteins in different diseases/ sub-types of disease
• proteins are ubiquitinated and (hyper-)phosphorylated

Question 23

most common aggregates in ALS

Answer 23

• SOD1
• TARDBP
  (one or the other)

Question 24

most common ALS mutations

Answer 24

• C9orf72
• SOD1

Question 25

most common insoluble protein inclusions found in motor neurons

Answer 25

• TDP-43

Question 26

note

Answer 26

• toxicity of misfolded/ aggregating proteins not fully understood