Overexpression of Heat Shock Factor 1 Protects against Pathological Proteins in Neurodegenerative Diseases

A classical feature of neurodegenerative disorders is the accumulation of protein aggregates, such as TAR DNA/RNA binding protein (TDP-43) and superoxide dismutase 1 (SOD1), which lead to neuronal dysfunction and loss. Therefore, molecules that maintain protein homeostasis may be beneficial therapeutic targets to correct the imbalance in protein folding and clearance in these disorders. Heat shock proteins (HSPs), such as HSP70 and HSP90 are molecular chaperones that maintain protein homeostasis and prevent neuronal death. HSPs are regulated by a stress-induced transcriptional factor, heat shock factor 1 (HSF1). HSF1 is inactive when in complex with HSP90 and becomes active once it is released from this interaction in the presence of misfolded proteins. Studies have shown that levels of multiple HSPs are reduced in the spinal cord of ALS patients, which suggests a decline in HSF1 activity, and could contribute to the accumulation of disease proteins. Targeted activation of HSF1 has raised tremendous interest as a potential target for therapeutic development. HSP90 inhibitors that target the HSF1-HSP90 complex, as well as drugs that are stress-induced HSF1 activators have been shown to prevent aggregation in neurodegeneration models; however, they also have toxic off-target effects. Furthermore, overexpression of constitutively active HSF1 reduced the accumulation of insoluble TDP-43 in cell culture; however, male mice overexpressing the active form had an infertility phenotype. This thesis reports that overexpression of wild-type HSF1 causes a robust induction of HSPs in response to proteotoxic stress, reduced toxicity and protected against TDP-43 and SOD1 disease-related pathology in cell culture and mice respectively. I have generated a new double transgenic mouse model to further investigate the protective mechanism of HSF1 overexpression against TDP-43 pathology, during the time of this work. The nuclear clearance of TDP-43 is a pathological phenotype seen in ALS and FTLD, and my preliminary studies have shown that HSF1 induced a two-fold increase in nuclear TDP-43 in these double transgenic mice. These results have laid the framework for further research. This thesis provides new data supporting the therapeutic efficacy of targeting HSF1 levels for the treatment of TDP-43 proteinopathies and ALS.