title: VPS35 regulates parkin substrate AIMP2 toxicity by facilitating lysosomal clearance of AIMP2.
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 α-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.
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA.
authors.forename: Seung Pil
authors.initials: SP
authors.lastname: Yun
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea.
authors.forename: Hyojung
authors.initials: H
authors.lastname: Kim
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea.
authors.forename: Sangwoo
authors.initials: S
authors.lastname: Ham
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: College of Pharmacy, Chosun University, Gwangju, Republic of Korea.
authors.forename: Gum Hwa
authors.initials: GH
authors.lastname: Lee
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea.
authors.forename: Joo-Ho
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Medical Science Research Institute, Soonchunhyang University, Seoul Hospital, Seoul, Republic of Korea.
authors.forename: Sang Hun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA.
authors.forename: Han Seok
authors.initials: HS
authors.lastname: Ko
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, South Korea.
authors.forename: Yunjong
authors.identifier: 0000-0003-0182-2279
authors.initials: Y
authors.lastname: Lee
mesh_terms: D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C575685:AIMP2 protein, human; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D009687:Nuclear Proteins; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1