How does a partial loss-of-function TDP-43 variant with high aggregation propensity cause dominant disease?

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Priority

82%

Importance

85%

Tractability

80%

Market price

50%

Description

The variant shows reduced toxic gain-of-function properties and can rescue null phenotypes, yet causes autosomal dominant myopathy. This paradox between loss-of-function behavior and dominant inheritance with high aggregation propensity lacks mechanistic explanation.

Gap type: unexplained_observation Source paper: C-terminal frameshift variant of TDP-43 with pronounced aggregation-propensity causes rimmed vacuole myopathy but not ALS/FTD. (2023, Acta neuropathologica, PMID:37000196)

Evidence summary

Resolved by hypothesis h-ccc05373: p38α Inhibitor and PRMT1 Activator Combination to Restore Physiological TDP-43 Phosphorylation-Methylation Balance. Score: 0.879. Supporting PMIDs: 39817908, NCT05869669, 39817908, NCT05869669, 39817908.

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