The Impact of Sex and Aging on Heat Shock Protein Induction in a Drosophila melanogaster Model of Glial Tauopathy



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Tauopathies are a family of neurodegenerative diseases, which include Alzheimer’s disease, frontotemporal lobe dementia, and progressive supranuclear palsy. This subclass of diseases is characterized by the aggregation of hyperphosphorylated tau in neurons and glia. Heat shock chaperone proteins (HSPs) are able to help maintain proteostasis by helping to monitor protein synthesis, folding, trafficking, assembly of quaternary structures, turnover, and clearance of toxic aggregates. However, these protective mechanisms are insufficient when responding to tau proteotoxicity. Further complicating the matter, many neurodegenerative diseases present sexual dimorphisms in their onset, progression, and severity. Additionally, studies have shown that certain HSPs can become overwhelmed by stress as the system ages, which in turn causes a decline in the global defense mechanism. As a result, this study seeks to uncover how glial tau aggregation, age, and sex concurrently impact the chaperone system by performing a holistic screening of HSP induction in a Drosophila melanogaster model. Our studies highlighted how each heat shock chaperone uniquely contributes to the proteostasis machinery. Responses to our experimental variables vary greatly across this protein family. Female flies seem to respond more globally to heat shock by itself or in combination with glial tau or aging stress. Male flies exhibit stronger responses to the simultaneous combination of all three stresses. Basal suppression of HSP27 and the age-dependency of HSP70 and HSP27’s upregulation in response to tau in females may indicate a predisposition towards disease, as these are crucial HSP pathways in glial cells. Further investigation into the causes of these sex-related differences is warranted to unravel the mechanisms behind the chaperone response to glial tau.



tauopathy, neurodegeneration, drosophila, protein misfolding, glia, sex, heat shock protein, protein aggregation, aging