Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1

Frederick C. Nucifora (), Leslie G. Nucifora, Chee-Hoe Ng, Nicolas Arbez, Yajuan Guo, Elaine Roby, Vered Shani, Simone Engelender, Dong Wei, Xiao-Fang Wang, Tianxia Li, Darren J. Moore, Olga Pletnikova, Juan C. Troncoso, Akira Sawa, Ted M. Dawson, Wanli Smith, Kah-Leong Lim and Christopher A. Ross
Additional contact information
Frederick C. Nucifora: Johns Hopkins University School of Medicine
Leslie G. Nucifora: Johns Hopkins University School of Medicine
Chee-Hoe Ng: Danone Nutricia Research
Nicolas Arbez: Johns Hopkins University School of Medicine
Yajuan Guo: Johns Hopkins University School of Medicine
Elaine Roby: Johns Hopkins University School of Medicine
Vered Shani: Rappaport Institute of Medical Research, Technion-Israel Institute of Technology
Simone Engelender: Rappaport Institute of Medical Research, Technion-Israel Institute of Technology
Dong Wei: Johns Hopkins University School of Medicine
Xiao-Fang Wang: Johns Hopkins University School of Medicine
Tianxia Li: University of Maryland School of Pharmacy
Darren J. Moore: Center for Neurodegenerative Science, Van Andel Research Institute
Olga Pletnikova: Johns Hopkins University School of Medicine
Juan C. Troncoso: Johns Hopkins University School of Medicine
Akira Sawa: Johns Hopkins University School of Medicine
Ted M. Dawson: Johns Hopkins University School of Medicine
Wanli Smith: University of Maryland School of Pharmacy
Kah-Leong Lim: Neuroscience and Behavioral Disorders Program, Duke-National University of Singapore Graduate Medical School
Christopher A. Ross: Johns Hopkins University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms11792

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