Motor Neuron Disease - Mechanisms Flashcards
What are the 3 main pathways involved in MND
Protein homeostasis
Altered RNA-binding proteins
Cytoskeletal proteins
What does ALS stand for?
Amyotrophic Lateral Sclerosis
What is the Aetiology of MND?
It is unknown
~95% of cases are “sporadic”
~5% genetically determined
What are the most common genes causing typical MND?
SOD1 - 20% frequency in FALS
C9ORF72 - 40% frequency in FALS
What is the protein that aggregates in MND?
TDP43 - inclusions of this protein found in ~95% of MND cases
How is MND characterized?
A mix of upper and lower motor neurone signs with fasciculation (involuntary rapid muscle twitches too weak to move a limb)
What is the locational onset of MND?
80% Limb Onset
20% Bulbar Onset
How is MND managed?
Palliative care from diagnosis to death
Average survival/prognosis for MND?
30-36 months from symptom onset
50% dead at 30 months
What is SOD1s protein function?
Metabolism of Reactive Oxygen Species (ROS) - antioxidant
Mutant SOD1 is transported to the mitochondria. Knowing that normal SOD1 is involved in ROS metabolism, how does this induce neurotoxicity?
Gaon of function of SOD1 Increase in ROS in motor neuron, ROS binds to Rac1/Nox2 on astrocytes and microglia.
What common conformational factor do most Mutated SOD1 proteins share?
An exposed N terminal which provokes ER stress by targeting an ER resident protein Derlin-1
Which form of SOD1 is thought to confer neurotoxicity?
Soluble SOD1
Increased concentration has be found to correlate with toxicity
What is the relationship of SOD1 and gene transctiption?
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.
What is TDP43?
A transactive DNA binding protein of 43KDA, coded for by TARDBP
How does mutant TDP-43 infer neurotoxicity?
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
What other protein complex does TDP43 form a stress granule with?
TIA1 with mRNA
Expansion of a GGGGCC hexanucleotide repeat in what gene causes chromosome 9p-linked ALS?
C9ORF72
What is the proposed gain of toxicity for C9ORF72?
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.
What DPR proteins are thought to be the most toxic?
Arginine-containing DPR proteins (poly(GR) and ploy (PR)). Reported damage to nucleolar structure, RNA processing and nucleocytoplasmic transport defects
What is the gain of toxicity hypothesis associated with the antisense RNAs in C9ORF72 expansion mutations?
Form nuclear/cytoplasmin repeat containing RNA Foci. Foci are proposed to sequester RNA-binding proteins and splicing factors causing RNA processing alterations
