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Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis

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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 SOD1G93A 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.

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Authors and Affiliations

  1. Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China

    Sheng Chen, Xiao-Jie Zhang, Li-Xi Li & Weidong Le

  2. Center for Translational Research on Neurological Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China

    Yin Wang, Ru-Jia Zhong & Weidong Le

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  1. Sheng Chen
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  2. Xiao-Jie Zhang
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  3. Li-Xi Li
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  4. Yin Wang
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  6. Weidong Le
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Correspondence to Weidong Le.

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Chen, S., Zhang, XJ., Li, LX. et al. Histone deacetylase 6 delays motor neuron degeneration by ameliorating the autophagic flux defect in a transgenic mouse model of amyotrophic lateral sclerosis. Neurosci. Bull. 31, 459–468 (2015). https://doi.org/10.1007/s12264-015-1539-3

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  • DOI: https://doi.org/10.1007/s12264-015-1539-3

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