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, Christopher A. Ross

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number11792
JournalNature communications
StatePublished - Jun 7 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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