FUS Phase Separation Dominance in FTD-TDP: Aberrant Condensate Hijacking of RNA…

In ALS motor neurons, disease-modified RBM45 hijacks RNA processing condensates through altered LLPS behavior, displacing TDP-43 into pathological aggregates. Similarly, in Frontotemporal dementia (particularly FTD-TDP subtype), FUS (Fused in Sarcoma) - another low-complexity domain RNA-binding protein - undergoes post-translational modifications (phosphorylation, acetylation) that stabilize its condensates at nuclear speckles and stress granules. These dominant FUS condensates may displace TDP-43 and hnRNP A1, driving TDP-43 aggregation pathology characteristic of FTD-TDP.

Analogy rationale: Both RBM45 and FUS are neuronal RNA-binding proteins with low-complexity domains that undergo LLPS. FUS is already implicated in FTD (mutations cause familial FTD/ALS), exhibits phase separation behavior, and its aggregates are found in a subset of FTD cases. The mechanistic logic of LCD-mediated condensate dominance transfers directly.

Disanalogies: RBM45 is predominantly cytoplasmic while FUS shuttles nucleocytoplasmically; FTD primarily affects cortical neurons whereas ALS affects motor neurons, which may alter condensate composition and vulnerability. Additionally, TDP-43 pathology in FTD may have distinct initiators beyond condensate displacement.

Falsifiable prediction: In iPSC-derived cortical neurons from FTD patients with FUS mutations, super-resolution microscopy will reveal co-localization of FUS liquid droplets with TDP-43 mislocalization prior to aggregation, and FRAP experiments will demonstrate slowed FUS droplet dynamics compared to controls, consistent with dominant aberrant condensates.

This hypothesis was generated from h-alsmnd-9d62ae58bdc1 in ALS — judge it on its own merits but acknowledge the source.