Impact of Sex and Glial Tau Expression on Heat Shock Protein Induction in a Drosophila Model of Tauopathy

Heat shock proteins (Hsps) are central components of the cellular stress response and serve as the first line of defense against protein misfolding and aggregation. Disruption of this proteostasis network is a hallmark of neurodegenerative diseases, including tauopathies, a class of neurodegenerative diseases characterized by intracellular tau accumulation in neuronal and glial cells. Although specific Hsps are enriched in glial cells, and some have been shown to directly bind tau and influence its aggregation, the broader interplay between Hsps and tau remains poorly understood. In particular, it is unclear whether tau expression affects the heat shock response and whether this interaction is modulated in a sex-specific fashion. Here, we used a Drosophila model of tauopathy to examine both inducible and constitutive Hsp expression in response to heat stress in the context of glial tau expression. We found that Hsp expression displays sexually dimorphic expression patterns at basal levels and in response to heat stress. Moreover, tau expression in glia disrupts the normal induction of specific heat shock proteins following heat stress. This work provides new insight into how tau interacts with the cellular stress response and highlights sex-specific differences in Hsp regulation. Understanding these molecular connections is crucial to understanding how the presence of tau in glial cells influences the stress response and potentially contributes to tauopathy pathogenesis.