Auxilin Underlies Progressive Locomotor Deficits and Dopaminergic Neuron Loss in a Drosophila Model of Parkinson's Disease

doi:10.1016/j.celrep.2017.01.005

. 2017 Jan 31;18(5):1132-1143.

doi: 10.1016/j.celrep.2017.01.005.

Auxilin Underlies Progressive Locomotor Deficits and Dopaminergic Neuron Loss in a Drosophila Model of Parkinson's Disease

Li Song¹, Yijing He², Jiayao Ou¹, Yongbo Zhao¹, Ruoyu Li¹, Jingjing Cheng¹, Chin-Hsien Lin³, Margaret S Ho⁴

Affiliations

¹ Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China; Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China; Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai 200092, China.
² Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xin-Cun Road, Shanghai 200065, China.
³ Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
⁴ Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China; Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China; Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai 200092, China. Electronic address: margaret_ho@tongji.edu.cn.

PMID: 28147270
DOI: 10.1016/j.celrep.2017.01.005

Free article

Auxilin Underlies Progressive Locomotor Deficits and Dopaminergic Neuron Loss in a Drosophila Model of Parkinson's Disease

Li Song et al. Cell Rep. 2017.

Free article

. 2017 Jan 31;18(5):1132-1143.

doi: 10.1016/j.celrep.2017.01.005.

Authors

Li Song¹, Yijing He², Jiayao Ou¹, Yongbo Zhao¹, Ruoyu Li¹, Jingjing Cheng¹, Chin-Hsien Lin³, Margaret S Ho⁴

Affiliations

¹ Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China; Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China; Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai 200092, China.
² Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xin-Cun Road, Shanghai 200065, China.
³ Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
⁴ Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China; Key Laboratory of Arrhythmias, Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai 200120, China; Department of Anatomy and Neurobiology, 1239 Siping Road, Tongji University School of Medicine, Shanghai 200092, China. Electronic address: margaret_ho@tongji.edu.cn.

PMID: 28147270
DOI: 10.1016/j.celrep.2017.01.005

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder that exhibits motor and non-motor symptoms, as well as pathological hallmarks, including dopaminergic (DA) neuron death and formation of α-synuclein (α-Syn) Lewy bodies. Cyclin-G-associated kinase (GAK), a PD susceptibility gene identified through genome-wide association studies (GWAS), is a ubiquitous serine/threonine kinase involved in clathrin uncoating, though its PD-related function remains elusive. Here, we implicate the Drosophila GAK homolog, auxilin (aux), in a broad spectrum of parkinsonian-like symptoms. Downregulating aux expression leads to progressive loss of climbing ability, decreased lifespan, and age-dependent DA neuron death similar to α-Syn overexpression. Reduced aux expression further enhances and accelerates α-Syn-mediated DA neuron loss. Flies with reduced aux expression are more sensitive to the toxin paraquat, suggesting that genetic and environmental factors intertwine. Taken together, these findings decipher a pivotal role for GAK/aux and suggest mechanisms underlying PD.

Keywords: DA; GAK; PD; Parkinson’s disease; aux; auxilin; cyclin-G-associated kinase; dopaminergic neuron loss; locomotor deficits; longevity; paraquat; α-synuclein.

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Auxilin Underlies Progressive Locomotor Deficits and Dopaminergic Neuron Loss in a Drosophila Model of Parkinson's Disease

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Auxilin Underlies Progressive Locomotor Deficits and Dopaminergic Neuron Loss in a Drosophila Model of Parkinson's Disease

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