TY - JOUR
T1 - Parkinson's disease-linked DNAJC13 mutation aggravates alpha-synuclein-induced neurotoxicity through perturbation of endosomal trafficking
AU - Yoshida, Shun
AU - Hasegawa, Takafumi
AU - Suzuki, Mari
AU - Sugeno, Naoto
AU - Kobayashi, Junpei
AU - Ueyama, Morio
AU - Fukuda, Mitsunori
AU - Ido-Fujibayashi, Akemi
AU - Sekiguchi, Kiyotoshi
AU - Ezura, Michinori
AU - Kikuchi, Akio
AU - Baba, Toru
AU - Takeda, Atsushi
AU - Mochizuki, Hideki
AU - Nagai, Yoshitaka
AU - Aoki, Masashi
N1 - Funding Information:
A Grant-in-Aid for Scientific Research (C) (17K09744) and a Grant-in-Aid for Scientific Research on Innovative Areas (Brain Protein Aging and Dementia Control) (17H05683) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT); a Grant-in-Aid for the Research Committee for Ataxic Diseases, a Grant-in-Aid for Practical Research Projects for Rare/ Intractable Diseases, a Grain-in-aid for Translational Research Network Program and a Grant-in-aid for the Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development (AMED); Novartis Pharma Research Grants.
Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press. All rights reserved.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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 α-synuclein (αSYN) pathology toward neurodegeneration remains poorly understood. In this study, we showed that PD-linked N855S-mutant DNAJC13 caused αSYN 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 aSYN transgenic flies showed that mutant DNAJC13 not only increased the amount of insoluble αSYN 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 αSYN, which might predispose to the neurodegenerative process that leads to PD.
AB - 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 α-synuclein (αSYN) pathology toward neurodegeneration remains poorly understood. In this study, we showed that PD-linked N855S-mutant DNAJC13 caused αSYN 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 aSYN transgenic flies showed that mutant DNAJC13 not only increased the amount of insoluble αSYN 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 αSYN, which might predispose to the neurodegenerative process that leads to PD.
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U2 - 10.1093/hmg/ddy003
DO - 10.1093/hmg/ddy003
M3 - Article
C2 - 29309590
AN - SCOPUS:85043454233
SN - 0964-6906
VL - 27
SP - 823
EP - 836
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 5
ER -
