Auxilin Underlies Progressive Locomotor Deficits and Dopaminergic Neuron Loss in a Drosophila Model of Parkinson's Disease.
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.
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.
Li
L
Song
Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xin-Cun Road, Shanghai 200065, China.
Yijing
Y
He
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.
Jiayao
J
Ou
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.
Yongbo
Y
Zhao
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.
Ruoyu
R
Li
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.
Jingjing
J
Cheng
Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Chin-Hsien
CH
Lin
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.
Margaret S
MS
Ho
D000818:Animals; D034021:Auxilins / Q000378:metabolism*; D002966:Clathrin / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D004330:Drosophila / Q000378:metabolism; D055106:Genome-Wide Association Study / Q000379:methods; D016631:Lewy Bodies / Q000378:metabolism; D008124:Locomotion / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
D034021:Auxilins; D002966:Clathrin; D051844:alpha-Synuclein; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine
DA; GAK; PD; Parkinson’s disease; aux; auxilin; cyclin-G-associated kinase; dopaminergic neuron loss; locomotor deficits; longevity; paraquat; α-synuclein