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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Behavior, Animal
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Brain / metabolism
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Brain / pathology
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Drosophila Proteins / metabolism*
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Drosophila melanogaster / metabolism
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HEK293 Cells
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Humans
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Intracellular Signaling Peptides and Proteins
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / toxicity
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Lewy Bodies / metabolism
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Lysine / metabolism*
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Mice
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NIH 3T3 Cells
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Neurons / drug effects
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Neurons / metabolism
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Neuroprotection* / drug effects
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Parkinson Disease / metabolism
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Parkinson Disease / pathology
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Phenotype
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Protein Aggregates*
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Protein Binding / drug effects
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Solubility
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination*
Substances
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Drosophila Proteins
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Intracellular Signaling Peptides and Proteins
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Protein Aggregates
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Wsb1 protein, mouse
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Ubiquitin-Protein Ligases
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Lysine