VPS35 regulates parkin substrate AIMP2 toxicity by facilitatinglysosomal clearance of AIMP2

Collection with item attached
2017
Item details URL
http://open-repository.kisti.re.kr/cube/handle/open_repository/486949.do
DOI
10.1038/cddis.2017.157
Title
VPS35 regulates parkin substrate AIMP2 toxicity by facilitatinglysosomal clearance of AIMP2
Description
This research was supported by a grant (SBRI, SMX1151191) funded bySamsung Biomedical Research Institute and a grant (2015R1C 1A1A01052708)of the Basic Science Research Program through the National ResearchFoundation of Korea (NRF) funded by the Ministry of Education, Republicof Korea. This work was supported by grants from the NIH/NINDS NS082205,NS098006 and NIH/NINDS NS38377 Morris K Udall Parkinson's DiseaseResearch Center. We acknowledge the joint participation by the AdrienneHelis Malvin Medical Research Foundation and the Diana Helis HenryMedical Research Foundation through its direct engagement in thecontinuous active conduct of medical research in conjunction with theJohns Hopkins Hospital and the Johns Hopkins University School ofMedicine and the Foundation's Parkinson's Disease Program H-1, H-2013.
abstract
Vacuolar protein sorting-associated protein 35 (VPS35) is involved in retrograde transport of proteins from endosomes to trans-Golgi network. Gene mutations in VPS35 are linked to autosomal dominant late-onset Parkinson's disease (PD). Although the identification of VPS35 mutations has provided novel insight about its interactions with several PD-associated genes including leucine-rich repeat kinase 2 (LRRK2) and a-synuclein, little information is available about the molecular mechanisms of cell death downstream of VPS35 dysfunction. In this study, we showed that VPS35 has a role in the lysosomal degradation of parkin substrate aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2), of which accumulation leads to poly (ADP-ribose) polymerase-1 (PARP1)-dependent cell death. VPS35 was co-immunoprecipitated with AIMP2, as well as lysosome-associated membrane protein-2a (Lamp2a). Interestingly, this association was disrupted by PD-associated VPS35 mutant D620N. VPS35 overexpression prevented AIMP2-potentiated cell death and PARP1 activation in SH-SY5Y cells. More importantly, knockdown of VPS35 led to PARP1 activation and cell death, which was AIMP2 dependent. These findings provide new mechanistic insights into the role of VPS35 in the regulation of AIMP2 levels and cell death. As AIMP2 accumulation was reported in PD patient's brains and involved in dopaminergic cell death, identification of VPS35 as a novel regulator of AIMP2 clearance via lysosomal pathway provides alternative venue to control dopaminergic cell death in PD.
provenance
Made available in Cube on 2018-09-28T16:21:14Z (GMT). No. of bitstreams: 0
language
English
author
Yun, Seung Pil
Kim, Hyojung
Ham, Sangwoo
Kwon, Seung-Hwan
Lee, Gum Hwa
Shin, Joo-Ho
Lee, Sang Hun
Ko, Han Seok
Lee, Yunjong
orcid
Lee, Yunjong/0000-0003-0182-2279; Ham, Sangwoo/0000-0003-4569-2584
accessioned
2018-09-28T16:21:14Z
available
2018-09-28T16:21:14Z
issued
2017
citation
CELL DEATH & DISEASE(8)
issn
2041-4889
uri
http://open-repository.kisti.re.kr/cube/handle/open_repository/486949.do
Funder
교육부
Funding Program
BK21플러스사업(0.5)
Project ID
1345274065
Jurisdiction
Rep.of Korea
Project Name
21st Century Biomedical Sciences Leader Development Program
rights
openAccess
type
article


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