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Up-regulation of autophagy-related gene 5 (ATG5) protects dopaminergic neurons in a zebrafish model of Parkinson's disease.
J Biol Chem. 2017 11 03; 292(44):18062-18074.JB

Abstract

Parkinson's disease (PD) is one of the most epidemic neurodegenerative diseases and is characterized by movement disorders arising from loss of midbrain dopaminergic (DA) neurons. Recently, the relationship between PD and autophagy has received considerable attention, but information about the mechanisms involved is lacking. Here, we report that autophagy-related gene 5 (ATG5) is potentially important in protecting dopaminergic neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in zebrafish. Using analyses of zebrafish swimming behavior, in situ hybridization, immunofluorescence, and expressions of genes and proteins related to PD and autophagy, we found that the ATG5 expression level was decreased and autophagy flux was blocked in this model. The ATG5 down-regulation led to the upgrade of PD-associated proteins, such as β-synuclein, Parkin, and PINK1, aggravation of MPTP-induced PD-mimicking pathological locomotor behavior, DA neuron loss labeled by tyrosine hydroxylase (TH) or dopamine transporter (DAT), and blocked autophagy flux in the zebrafish model. ATG5 overexpression alleviated or reversed these PD pathological features, rescued DA neuron cells as indicated by elevated TH/DAT levels, and restored autophagy flux. The role of ATG5 in protecting DA neurons was confirmed by expression of the human atg5 gene in the zebrafish model. Our findings reveal that ATG5 has a role in neuroprotection, and up-regulation of ATG5 may serve as a goal in the development of drugs for PD prevention and management.

Authors+Show Affiliations

From the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.From the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.From the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China zhangjingpu@imb.pumc.edu.cn zjp5577@126.com.From the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28928221

Citation

Hu, Zhan-Ying, et al. "Up-regulation of Autophagy-related Gene 5 (ATG5) Protects Dopaminergic Neurons in a Zebrafish Model of Parkinson's Disease." The Journal of Biological Chemistry, vol. 292, no. 44, 2017, pp. 18062-18074.
Hu ZY, Chen B, Zhang JP, et al. Up-regulation of autophagy-related gene 5 (ATG5) protects dopaminergic neurons in a zebrafish model of Parkinson's disease. J Biol Chem. 2017;292(44):18062-18074.
Hu, Z. Y., Chen, B., Zhang, J. P., & Ma, Y. Y. (2017). Up-regulation of autophagy-related gene 5 (ATG5) protects dopaminergic neurons in a zebrafish model of Parkinson's disease. The Journal of Biological Chemistry, 292(44), 18062-18074. https://doi.org/10.1074/jbc.M116.764795
Hu ZY, et al. Up-regulation of Autophagy-related Gene 5 (ATG5) Protects Dopaminergic Neurons in a Zebrafish Model of Parkinson's Disease. J Biol Chem. 2017 11 3;292(44):18062-18074. PubMed PMID: 28928221.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Up-regulation of autophagy-related gene 5 (ATG5) protects dopaminergic neurons in a zebrafish model of Parkinson's disease. AU - Hu,Zhan-Ying, AU - Chen,Bo, AU - Zhang,Jing-Pu, AU - Ma,Yuan-Yuan, Y1 - 2017/09/19/ PY - 2016/10/26/received PY - 2017/08/27/revised PY - 2017/9/21/pubmed PY - 2017/11/29/medline PY - 2017/9/21/entrez KW - PTEN-induced putative kinase 1 (PINK1) KW - Parkin KW - Parkinson disease KW - atg5 KW - autophagy KW - neurodegenerative disease KW - zebrafish KW - α-synuclein SP - 18062 EP - 18074 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 292 IS - 44 N2 - Parkinson's disease (PD) is one of the most epidemic neurodegenerative diseases and is characterized by movement disorders arising from loss of midbrain dopaminergic (DA) neurons. Recently, the relationship between PD and autophagy has received considerable attention, but information about the mechanisms involved is lacking. Here, we report that autophagy-related gene 5 (ATG5) is potentially important in protecting dopaminergic neurons in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in zebrafish. Using analyses of zebrafish swimming behavior, in situ hybridization, immunofluorescence, and expressions of genes and proteins related to PD and autophagy, we found that the ATG5 expression level was decreased and autophagy flux was blocked in this model. The ATG5 down-regulation led to the upgrade of PD-associated proteins, such as β-synuclein, Parkin, and PINK1, aggravation of MPTP-induced PD-mimicking pathological locomotor behavior, DA neuron loss labeled by tyrosine hydroxylase (TH) or dopamine transporter (DAT), and blocked autophagy flux in the zebrafish model. ATG5 overexpression alleviated or reversed these PD pathological features, rescued DA neuron cells as indicated by elevated TH/DAT levels, and restored autophagy flux. The role of ATG5 in protecting DA neurons was confirmed by expression of the human atg5 gene in the zebrafish model. Our findings reveal that ATG5 has a role in neuroprotection, and up-regulation of ATG5 may serve as a goal in the development of drugs for PD prevention and management. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/28928221/Up_regulation_of_autophagy_related_gene_5__ATG5__protects_dopaminergic_neurons_in_a_zebrafish_model_of_Parkinson's_disease_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=28928221 DB - PRIME DP - Unbound Medicine ER -