TY - JOUR
T1 - Histone deacetylase 6 regulates cytotoxic α-synuclein accumulation through induction of the heat shock response
AU - Du, Yunlan
AU - Wang, Fei
AU - Zou, Jing
AU - Le, Weidong
AU - Dong, Qing
AU - Wang, Zhiying
AU - Shen, Fei
AU - Yu, Ling
AU - Li, Yansheng
PY - 2014/10
Y1 - 2014/10
N2 - 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 invitro 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.
AB - 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 invitro 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.
KW - Heat shock
KW - Histone deacetylase 6
KW - Parkinson's disease
KW - Ubiquitin-proteasome system
KW - α-synuclein
UR - http://www.scopus.com/inward/record.url?scp=84903817087&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903817087&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2014.04.029
DO - 10.1016/j.neurobiolaging.2014.04.029
M3 - Article
C2 - 24866403
AN - SCOPUS:84903817087
VL - 35
SP - 2316
EP - 2328
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 10
ER -