Histone deacetylase 6 regulates cytotoxic α-synuclein accumulation through induction of the heat shock response

Abnormal aggregation of α-synuclein (α-syn) is central to the pathogenesis of Parkinson's disease (PD). Histone deacetylase 6 (HDAC6) was previously shown to control major cell response pathways to the cytotoxic ubiquitinated aggregates in some protein aggregation diseases. Whether it influences the aggregation process of α-syn in PD models and its related mechanisms are not completely known. Here, we characterized the expression and function of HDAC6 in the ubiquitin-proteasome system impairment-induced PD model. Our results showed that HDAC6 inhibition further exacerbated the nigrostriatal dopamine neurodegeneration and upregulated α-syn oligomers levels, whereas HDAC6 overexpression in vitro showed the opposite effects. More importantly, we provided evidence for the first time that HDAC6 regulating α-syn oligomers levels were related to its ability to trigger the heat shock response in a heat shock protein 90-dependent manner. HDAC6 mediated the dissociation of heat shock protein 90-heat shock factor 1-containing complex, and the activation of heat shock factor 1, which led to the expression of major molecular chaperones to prevent the deleterious α-syn aggregation. Thus, we propose that HDAC6 appears as a key modulator of cell protective response to the cytotoxic α-syn aggregates and may serve as a potential target for therapy development in PD.