TDP-43 Liquid-Liquid Phase Separation Dominance in Stress Granules Predisposes to Pathological Aggregation in Alzheimer's Disease

Modified TDP-43 (phosphorylation, ubiquitination) in AD neurons undergoes altered LLPS behavior, forming pathologically stable stress granules that outcompete transient, functional granules. This TDP-43 condensate dominance displaces essential RNA processing factors (TIA1, G3BP1, hnRNP A1) into aggregation-prone states, mirroring the RBM45 hijacking mechanism observed in ALS. The prediction is that AD-associated TDP-43 modifications increase stress granule dwell time and promote co-aggregation of displaced components.

Analogy rationale: TDP-43 pathology occurs in both ALS and AD; both diseases show altered phase separation behavior of RNA-binding proteins leading to pathological aggregation. TDP-43 in AD shows similar post-translational modifications (phosphorylation, ubiquitination) that could alter LLPS behavior as demonstrated for RBM45 in ALS.

Disanalogies: AD pathology is dominated by Aβ plaques and tau tangles rather than TDP-43 aggregates; AD progression is slower and involves different regional vulnerability (hippocampal vs. motor). Additionally, AD predominantly affects glia and involves chronic inflammation not central to the ALS model.

Modified TDP-43 (phosphorylation, ubiquitination) in AD neurons undergoes altered LLPS behavior, forming pathologically stable stress granules that outcompete transient, functional granules. This TDP-43 condensate dominance displaces essential RNA processing factors (TIA1, G3BP1, hnRNP A1) into aggregation-prone states, mirroring the RBM45 hijacking mechanism observed in ALS. The prediction is that AD-associated TDP-43 modifications increase stress granule dwell time and promote co-aggregation of displaced components.

Analogy rationale: TDP-43 pathology occurs in both ALS and AD; both diseases show altered phase separation behavior of RNA-binding proteins leading to pathological aggregation. TDP-43 in AD shows similar post-translational modifications (phosphorylation, ubiquitination) that could alter LLPS behavior as demonstrated for RBM45 in ALS.

Disanalogies: AD pathology is dominated by Aβ plaques and tau tangles rather than TDP-43 aggregates; AD progression is slower and involves different regional vulnerability (hippocampal vs. motor). Additionally, AD predominantly affects glia and involves chronic inflammation not central to the ALS model.

Falsifiable prediction: TDP-43 extracted from AD brain tissue (vs. age-matched controls) will show increased viscosity and decreased FRAP recovery rate in condensate assays, correlating with the extent of AD pathology and phosphorylation status at known ALS-linked sites (S409/410).
This hypothesis was generated from `h-alsmnd-9d62ae58bdc1` in `ALS` — judge it on its own merits but acknowledge the source.