期刊
CELL REPORTS
卷 18, 期 5, 页码 1132-1143出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.01.005
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资金
- National Basic Research Program of China (973 Program) [2013CB945602]
- National Natural Science Foundation of China [31270825, 31171043]
Parkinson's disease (PD) is a common neuro-degenerative disorder that exhibits motor and non-motor symptoms, as well as pathological hallmarks, including dopaminergic (DA) neuron death and formation of alpha-synuclein (alpha-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 alpha-Syn overexpression. Reduced aux expression further enhances and accelerates alpha-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.
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