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

doi:10.1038/ncomms11792

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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.

Original language	English (US)
Article number	11792
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11792
State	Published - Jun 7 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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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. Nature communications, 7, Article 11792. https://doi.org/10.1038/ncomms11792

Nucifora, FC , Nucifora, LG, Ng, CH, Arbez, N, Guo, Y, Roby, E, Shani, V, Engelender, S, Wei, D, Wang, XF, Li, T, Moore, DJ, Pletnikova, O, Troncoso, JC , Sawa, A , Dawson, TM , Smith, W, Lim, KL & Ross, CA 2016, 'Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1', Nature communications, vol. 7, 11792. https://doi.org/10.1038/ncomms11792

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title = "Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1",

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.",

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

year = "2016",

month = jun,

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doi = "10.1038/ncomms11792",

language = "English (US)",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

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T1 - Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1

AU - Nucifora, Frederick C.

AU - Nucifora, Leslie G.

AU - Ng, Chee Hoe

AU - Arbez, Nicolas

AU - Guo, Yajuan

AU - Roby, Elaine

AU - Shani, Vered

AU - Engelender, Simone

AU - Wei, Dong

AU - Wang, Xiao Fang

AU - Li, Tianxia

AU - Moore, Darren J.

AU - Pletnikova, Olga

AU - Troncoso, Juan C.

AU - Sawa, Akira

AU - Dawson, Ted M.

AU - Smith, Wanli

AU - Lim, Kah Leong

AU - Ross, Christopher A.

PY - 2016/6/7

Y1 - 2016/6/7

N2 - 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.

AB - 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.

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

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