WK11 - MND

Question 1

What is MND

Answer 1

Progressive loss of UMN + LMN
* Incurable
* Survival ~2-3y after diagnosis

Question 2

Symptoms and progression of MND

Answer 2

1. Muscle: cramps, weakness and wastage
2. Rapid paralysis
3. Difficulty movement, speech, swallowing
4. Loss inervation of diaphragm

Question 3

Burden of MND in Australia

Answer 3

$2.4 billion (2015)
* >400k GLOBAL
* 2K AUS

Question 4

Incidence of MND

Answer 4

Appears to be increasing
* Better detection?
* Longer survival times?)

Question 5

Riluzole (2014)

Answer 5

1st drug for MND
* Extends survival by 6-19m
* No major symptom improvements
* Hyperexcitability is managed by this drug

Question 6

Edavarone (2023)

Answer 6

Repurposed stroke medication
* Slowed progression only in early stage and subsets
* Antioxidant

Question 7

Relyvrio (X)

Answer 7

Combination
* failed to pass Phase 3 clinical trials
* Not approv. in AUS

Question 8

SOD1

Answer 8

1st gene associated w/ MND
* prevalence is prob why it was caught earlier

Question 9

C9ORF72 in MND

Answer 9

45% of familial cases
* HIGH PREVALENCE

Question 10

TDP-43 mutant and WT

Answer 10

BOTH causative of MND
* Mutant > Familial
* WT > Sporadic

Question 11

Mutations in SPORADIC MND

Answer 11

Mutations in C9orf72 or SOD1 occur sporadically in same genes as familial.

Question 12

Genetic variation in MND

Answer 12

Influences phenotypic manifestations:
* onset age
* site of symptom onset
* Progression rate.

Question 13

Electromyography (EMG) and nerve conduction studies

Answer 13

Assesses health of muscles and the nerves innervating them
* track MND progression

Question 14

Ultrasound in MND

Answer 14

Detection of fasciculations from multiple muscles

Question 15

Fasiculations

Answer 15

visible, spontaneous twitches of muscle fibers

Question 16

Biofluids (blood and CSF) in MND

Answer 16

Tracking neurofilament levels over time, marker of axonal degeneration, not specific

Question 17

Process of TDP-43 inclusion formation in MND

Answer 17

1. Loss of WT TDP-43 from nucleus.
2. Accumulation in cytoplasm > protein misfolding, truncation, PTMs
3. Inclusion formation.

Question 18

Molecular mechanism behind TDP-43 in MND

Answer 18

1. Impaired proteostasis
2. ER stress

Question 19

Heat shock response (HSR)

Answer 19

Transcriptional mechanism that boosts levels of chaperone proteins (heat shock proteins; HSPs) in stress
* involved in proteostasis

Question 20

Autophagy lysosome pathway (ALP) and ubiquitin proteasome system (UPS)

Answer 20

Ubiquitinate, recruit, then degrade proteins
* involved in proteostasis

Question 21

DNAJB5

Answer 21

DNAJB5 over-expression significantly decreases TDP-43 aggregation
* Resolubilise into a functional form

Question 22

DNAJB5 knockout mice

Answer 22

Didn’t have the strength to perform reflex
* TDP-43-mediated disease worsened by knockout

Question 23

Targeting mutant SOD1 in familial MND

Answer 23

Antisense oligonucleotide (ASO “Toferson”) that targets mRNA from mutated SOD1
* decreases lvls

Question 24

Outcomes of ASOs

Answer 24

Decrease in CSF SOD1 (35%) and NFL (50%).
* Early treatment = slower decline