Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1.
A common genetic form of Parkinson's disease (PD) is caused by mutations in LRRK2. We identify WSB1 as a LRRK2 interacting protein. WSB1 ubiquitinates LRRK2 through K27 and K29 linkage chains, leading to LRRK2 aggregation and neuronal protection in primary neurons and a Drosophila model of G2019S LRRK2. Knocking down endogenous WSB1 exacerbates mutant LRRK2 neuronal toxicity in neurons and the Drosophila model, indicating a role for endogenous WSB1 in modulating LRRK2 cell toxicity. WSB1 is in Lewy bodies in human PD post-mortem tissue. These data demonstrate a role for WSB1 in mutant LRRK2 pathogenesis, and suggest involvement in Lewy body pathology in sporadic PD. Our data indicate a role in PD for ubiquitin K27 and K29 linkages, and suggest that ubiquitination may be a signal for aggregation and neuronal protection in PD, which may be relevant for other neurodegenerative disorders. Finally, our study identifies a novel therapeutic target for PD.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Frederick C
FC
Nucifora
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Leslie G
LG
Nucifora
Danone Nutricia Research, 30 Biopolis Street, Matrix Building, #05-01B, Singapore 138671, Singapore.
Chee-Hoe
CH
Ng
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Nicolas
N
Arbez
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Yajuan
Y
Guo
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Elaine
E
Roby
Department of Molecular Pharmacology, Rappaport Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Vered
V
Shani
Department of Molecular Pharmacology, Rappaport Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
Simone
S
Engelender
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Dong
D
Wei
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Xiao-Fang
XF
Wang
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, USA.
Tianxia
T
Li
Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
Darren J
DJ
Moore
Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA.
Olga
O
Pletnikova
Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA.
Juan C
JC
Troncoso
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA.
Akira
A
Sawa
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA.|Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA.|Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA.|Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685, USA.
Ted M
TM
Dawson
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, USA.
Wanli
W
Smith
Neuroscience and Behavioral Disorders Program, Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore.|Department of Physiology, National University of Singapore, Singapore 117543, Singapore.
Kah-Leong
KL
Lim
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21201, USA.
Christopher A
CA
Ross
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000378:metabolism* / Q000633:toxicity; D016631:Lewy Bodies / Q000378:metabolism; D008239:Lysine / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D066329:Protein Aggregates; D011485:Protein Binding / Q000187:drug effects; D012995:Solubility; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D066329:Protein Aggregates; C503398:Wsb1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008239:Lysine