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

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Li Song, Yijing He, Jiayao Ou, Yongbo Zhao, Ruoyu Li, Jingjing Cheng, Chin-Hsien Lin, Margaret S. Ho
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.

Graphical abstract

Teaser

Parkinson's disease (PD) is a neurodegenerative disorder that exhibits motor symptoms and neuron loss. Song et al. implicate Drosophila cyclin-G-associated kinase (GAK) in fly phenotypes reminiscent of PD.


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