Welander Distal Myopathy-Associated TIA1 E384K Mutation Disrupts Stress Granule Dynamics Under Distinct Stress Conditions.

Abstract

Cellular stress triggers the formation of diverse RNA-protein aggregates, which can be associated with physiological responses, pathological conditions, or even detrimental outcomes. Under stress-induced proteostasis disruption, these RNA-protein assemblies are known as stress granules (SGs). Targeting such condensates-while sparing functional RNAs and proteins-remains a major therapeutic challenge in protein aggregation disorders such as myopathies and neuropathies. In this study, we investigated the cellular response to various stress conditions in the context of the TIA1 E384K mutation, a founder variant implicated in both Welander distal myopathy (WDM) and amyotrophic lateral sclerosis (ALS). Cells were exposed to different stressors, including proteotoxic, proteostatic, chemotoxic, and osmotic insults, and the behavior of TIA1-related SGs was analyzed. Our findings reveal a distinct yet conserved pattern in the dynamics of TIA1-dependent SG formation and clearance, influenced by the specific type of stressor and modulated by eIF2α Ser35 phosphorylation. These results indicate that the WDM-associated TIA1 mutation leads to aberrant SG dynamics across different stress conditions. Collectively, these observations support the idea that TIA1 E384K-associated SG dysregulation plays a role in WDM and ALS pathogenesis and underscores the importance of multiple stress contexts in disease progression.