TIA1 AS A CRITICAL MOLECULAR LINK BETWEEN RNA GRANULE DYNAMICS, NEURONAL ACTIVITY, AND BEHAVIOR

Chronic stress is a major risk factor for depression and accelerates neurodegeneration by promoting maladaptive cellular responses, including dysregulated RNA metabolism, Tau pathology, and synaptic dysfunction. We have demonstrated that prolonged stress alters Stress Granule (SG) dynamics in a Tau-dependent manner, shifting these dynamics from adaptive to aggregation-prone. Using P301L-Tau transgenic (P301L), Tau knockout (Tau-KO), and wild-type (WT) mice exposed to a 6-week chronic unpredictable stress protocol, we identified the RNA-binding protein TIA1 as a central mediator of the Tau-dependent stress response. While the absence of Tau abolished stress-induced TIA1 accumulation and SG formation, abnormal hTau elicited nuclear-to-cytoplasmic translocation of TIA1 and other RBPs, accompanied by cognitive and emotional deficits.
To assess the functional contribution of TIA1 for neuronal function, we used conditional knockout mouse models to target hippocampal neurons. Behavioural analyses revealed that TIA1 depletion altered cognitive performance, including exacerbated freezing response in contextual fear conditioning and decreased discrimination index in the NOR test. Fibre photometry recordings in the dorsal hippocampus further revealed changes in neuronal activity dynamics in TIA1-cKO mice, indicating a role for TIA1 in neuronal function in vivo. Despite these functional alterations, loss of TIA1 was overall protective under chronic stress conditions, with stressed TIA1-cKO mice showing improved cognitive outcomes.
Together, these results identify TIA1 as a molecular link between stress-induced RNA granule dynamics, neuronal activity, and memory, highlighting its relevance for understanding stress-related neurodegeneration and identifying a potential novel therapeutic target for stress-related brain pathologies.