Motor Neuron Disease - Mechanisms

Question 1

What are the 3 main pathways involved in MND

Answer 1

Protein homeostasis
Altered RNA-binding proteins
Cytoskeletal proteins

Question 2

What does ALS stand for?

Answer 2

Amyotrophic Lateral Sclerosis

Question 3

What is the Aetiology of MND?

Answer 3

It is unknown
~95% of cases are “sporadic”
~5% genetically determined

Question 4

What are the most common genes causing typical MND?

Answer 4

SOD1 - 20% frequency in FALS
C9ORF72 - 40% frequency in FALS

Question 5

What is the protein that aggregates in MND?

Answer 5

TDP43 - inclusions of this protein found in ~95% of MND cases

Question 6

How is MND characterized?

Answer 6

A mix of upper and lower motor neurone signs with fasciculation (involuntary rapid muscle twitches too weak to move a limb)

Question 7

What is the locational onset of MND?

Answer 7

80% Limb Onset
20% Bulbar Onset

Question 8

How is MND managed?

Answer 8

Palliative care from diagnosis to death

Question 9

Average survival/prognosis for MND?

Answer 9

30-36 months from symptom onset
50% dead at 30 months

Question 10

What is SOD1s protein function?

Answer 10

Metabolism of Reactive Oxygen Species (ROS) - antioxidant

Question 11

Mutant SOD1 is transported to the mitochondria. Knowing that normal SOD1 is involved in ROS metabolism, how does this induce neurotoxicity?

Answer 11

Gaon of function of SOD1 Increase in ROS in motor neuron, ROS binds to Rac1/Nox2 on astrocytes and microglia.

Question 12

What common conformational factor do most Mutated SOD1 proteins share?

Answer 12

An exposed N terminal which provokes ER stress by targeting an ER resident protein Derlin-1

Question 13

Which form of SOD1 is thought to confer neurotoxicity?

Answer 13

Soluble SOD1
Increased concentration has be found to correlate with toxicity

Question 14

What is the relationship of SOD1 and gene transctiption?

Answer 14

Wt SOD1 when phosphorylated binds promotors and regulates expression of oxidative resistance and repair genes. Mutant SOD1 has shown to be completely cleared from the nucleus and distributed mainly in cytoplasm, indicating a loss of transcriptomic function.

Question 15

What is TDP43?

Answer 15

A transactive DNA binding protein of 43KDA, coded for by TARDBP

Question 16

How does mutant TDP-43 infer neurotoxicity?

Answer 16

Loss of nuclear function - (gain of splicing functions, loss of promotor silencing)
Loss of NMJ integrity
Mislocalization and stress granule formation (NOT AGGREGATION)
Toxic at isogenic levels of expression without aggregation

Question 17

What other protein complex does TDP43 form a stress granule with?

Answer 17

TIA1 with mRNA

Question 18

Expansion of a GGGGCC hexanucleotide repeat in what gene causes chromosome 9p-linked ALS?

Answer 18

C9ORF72

Question 19

What is the proposed gain of toxicity for C9ORF72?

Answer 19

Accumalation of aberrant dipeptide-repeat (DPR) proteins encoded by repeat-containing RNAs. Aggregated of these DPR, which recruit p62, have been found in post-mortem tissue for patients with FALS.

Question 20

What DPR proteins are thought to be the most toxic?

Answer 20

Arginine-containing DPR proteins (poly(GR) and ploy (PR)). Reported damage to nucleolar structure, RNA processing and nucleocytoplasmic transport defects

Question 21

What is the gain of toxicity hypothesis associated with the antisense RNAs in C9ORF72 expansion mutations?

Answer 21

Form nuclear/cytoplasmin repeat containing RNA Foci. Foci are proposed to sequester RNA-binding proteins and splicing factors causing RNA processing alterations