Tau-Induced Suppression of Chaperone Stress Response in a Drosophila Model of Glial Tauopathy



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Filamentous inclusions of the protein tau in neuronal and glial cells characterize neurodegenerative tauopathies, such as Alzheimer’s disease (AD). The presence of these tau aggregates implies a dysfunction in the chaperone system, the cellular machinery responsible for preventing abnormal accumulation of misfolded proteins. One family of chaperone proteins, heat-shock proteins (HSPs), are synthesized at higher levels in response to cellular stress, and are capable of preventing and repairing protein damage. A promising therapeutic target, these HSPs are among the most potent suppressors of neurodegeneration in animal models, as their upregulation has been shown to prevent and even reverse disease pathology. Why then are endogenous chaperones unable to prevent the protein malfunction and aggregation that characterizes these disorders? Evidence suggests that an age-dependent decline and/or disease-related dysfunction in the protein quality control system may be to blame. In order to better understand heat-shock protein expression in aging and in neurodegenerative disease, a time-course of HSP expression at the mRNA level over the lifespan of the fly was investigated in a Drosophila melanogaster model of glial tauopathy and in control flies lacking the tau transgene. Control flies exposed to chronic thermal stress showed an age-dependent attenuation of HSP expression, supporting past evidence of age-related decline in the protein quality control system. Additionally, we observed dramatic, targeted suppression of the chaperone stress response in flies expressing tau in glial cells, suggesting a possible mechanism of tau-induced toxicity in AD and other tauopathies.


Recipient of the Ruth Estelle Mills Zencey Award for excellence in scientific writing.


tau, tauopathy, Alzheimer's disease, chaperone system, HSP, glia, neurodegenerative disease, Drosophila