Nucifora, F.C., Nucifora, L.G., Ng, C.H., Arbez, N., Guo, Y., Roby, E., Shani, V., Engelender, S., Wei, D., Wang, X.F., Li, T., Moore, D.J., Pletnikova, O., Troncoso, J.C., Sawa, A., Dawson, T.M., Smith, W., Lim, K.L., Ross, C.A. (2016). Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1.  Nat. Commun. 7(): 11792.

FBrf0232598

Research paper

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.

PMC4899630 (PMC) (EuropePMC)