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

Frederick C Nucifora,Chee-Hoe Ng,Nicolas Arbez,Olga Pletnikova,Darren J Moore,Wanli Smith,Akira Sawa,Dong Wei,Leslie G Nucifora,Xiao-Fang Wang,Elaine Roby,Ted M Dawson,Tianxia Li,Yajuan Guo,Juan C Troncoso,Kah-Leong Lim,Vered Shani,Christopher A Ross,Simone Engelender

doi:10.1038/ncomms11792

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.

Highlights

A common genetic form of Parkinson’s disease (PD) is caused by mutations in leucine-rich repeat kinase 2 protein (LRRK2)
To confirm that LRRK2 interacts with WSB1, we co-transfected full-length LRRK2 with full-length WSB1 in HEK 293 cells, and showed that WSB1 and LRRK2 co-immunoprecipitated (Fig. 1a,b)
We demonstrate that endogenous LRRK2 and endogenous WSB1 interact in NIH 3T3 mouse embryonic fibroblast cells (Fig. 1c)

Summary

Introduction

A common genetic form of Parkinson’s disease (PD) is caused by mutations in LRRK2. We identify WSB1 as a LRRK2 interacting protein. 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. Proteins fated for degradation are tagged with ubiquitin through the formation of an iso-peptide bond between the e-amino group of a lysine residue of the substrate and the C-terminal carboxylate of ubiquitin. This ligation reaction is a process requiring a repeated series of actions involving ubiquitin-activating (E1), -conjugating (E2) and -ligating (E3) enzymes, polyubiquitinating a protein[6]. Parkin is an E3 ligase[15,16,17] and has been shown to function as part of an E3 ligase complex with the PTEN-induced kinase (PINK1) and DJ-1 (ref. 18)

Methods

Results

Conclusion