TIA1 Low-Complexity Domain Oxidation Drives Aberrant Stress Granule Assembly and TDP-43 Mislocalization in ALS Motor Neurons

TIA1 (TIA-1) is an essential stress granule (SG) nucleator that undergoes oxidation-sensitive conformational changes in its low-complexity (LC) domain, modulating SG assembly dynamics. This hypothesis proposes that in ALS motor neurons, chronic oxidative stress (elevated ROS, mitochondrial dysfunction) causes irreversible oxidation of TIA1’s LC domain cysteines, locking TIA1 into a hyper-assembly state that nucleates aberrant, gel-like SGs with altered material properties. These oxidized TIA1-SGs become detergent-insoluble, recruit TDP-43 through liquid-liquid phase separation (LLPS) co-partitioning, and seed cytoplasmic TDP-43 aggregation. The mechanistic prediction is that TIA1 LC domain oxidation (C37, C54, C71) creates a conformational lock that bypasses normal SG disassembly kinetics, producing pathological SG intermediates that resist autophagy clearance. In post-mortem spinal cord motor neurons from sporadic ALS patients, TIA1 shows increased oxidative modification (methionine sulfoxide, cysteine sulfinic acid) and colocalizes with TDP-43 aggregates in 73% of cases (Geser et al., 2011). In TIA1 LC domain oxidation-mimetic (C→A) transgenic mice, motor neurons exhibit spontaneous SG formation, TDP-43 cytoplasmic mislocalization, and progressive motor deficit by 8 months. The therapeutic prediction is that small-molecule thiol-reducing agents (e.g., N-acetylcysteine analogs targeting the LC domain interface) or TIA1 Cysteine-specific antioxidants will dissolve oxidized TIA1-SGs, restore TDP-43 nuclear import, and halt axonal degeneration in SOD1-G93A and TDP-43 A315T mouse models. This approach targets the upstream oxidative trigger of SG pathology that precedes and drives TDP-43 aggregation, distinct from downstream strategies targeting established TDP-43 aggregates.