Parkinson's disease-linked DNAJC13 mutation aggravates alpha-synuclein-induced neurotoxicity through perturbation of endosomal trafficking

作者：Yoshida Shun; Hasegawa Takafumi^*; Suzuki Mari; Sugeno Naoto; Kobayashi Junpei; Ueyama Morio; Fukuda Mitsunori; Ido Fujibayashi Akemi; Sekiguchi Kiyotoshi; Ezura Michinori; Kikuchi Akio; Baba Toru; Takeda Atsushi; Mochizuki Hideki; Nagai Yoshitaka; Aoki Masashi

来源：Human Molecular Genetics, 2018, 27(5): 823-836.

DOI：10.1093/hmg/ddy003

Mutations in DNAJC13 gene have been linked to familial form of Parkinson's disease (PD) with Lewy pathology. DNAJC13 is an endosome-related protein and believed to regulate endosomal membrane trafficking. However, the mechanistic link between DNAJC13 mutation and alpha-synuclein (alpha SYN) pathology toward neurodegeneration remains poorly understood. In this study, we showed that PD-linked N855S-mutant DNAJC13 caused alpha SYN accumulation in the endosomal compartment, presumably due to defective cargo trafficking from the early endosome to the late and/or recycling endosome. In vivo experiments using human alpha SYN transgenic flies showed that mutant DNAJC13 not only increased the amount of insoluble alpha SYN in fly head but also induced dopaminergic neurodegeneration, rough eye phenotype and age-dependent locomotor impairment. Together, these findings suggest that DNAJC13 mutation perturbs multi-directional endosomal trafficking, resulting in the aberrant endosomal retention of alpha SYN, which might predispose to the neurodegenerative process that leads to PD.

• 出版日期2018-3-1
• 单位河北医科大学