title: Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motor neurons. Abnormal protein aggregation and impaired protein degradation are believed to contribute to the pathogenesis of this disease. Our previous studies showed that an autophagic flux defect is involved in motor neuron degeneration in the SOD1(G93A) mouse model of ALS. Histone deacetylase 6 (HDAC6) is a class II deacetylase that promotes autophagy by inducing the fusion of autophagosomes to lysosomes. In the present study, we showed that HDAC6 expression was decreased at the onset of disease and became extremely low at the late stage in ALS mice. Using lentivirus-HDAC6 gene injection, we found that HDAC6 overexpression prolonged the lifespan and delayed the motor neuron degeneration in ALS mice. Moreover, HDAC6 induced the formation of autolysosomes and accelerated the degradation of SOD1 protein aggregates in the motor neurons of ALS mice. Collectively, our results indicate that HDAC6 has neuroprotective effects in an animal model of ALS by improving the autophagic flux in motor neurons, and autophagosome-lysosome fusion might be a therapeutic target for ALS.
authors.affiliation: Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Chen
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Zhang
authors.forename: Li-Xi
authors.initials: LX
authors.lastname: Li
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.forename: Ru-Jia
authors.initials: RJ
authors.lastname: Zhong
authors.forename: Weidong
authors.initials: W
authors.lastname: Le
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology*; D000818:Animals; D001343:Autophagy; D005822:Genetic Vectors; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008297:Male; D064688:Metabolic Flux Analysis; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology*; D013116:Spinal Cord / Q000201:enzymology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases