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

Nat Commun. 2016 Jun 7;7:11792. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Brain / metabolism
  • Brain / pathology
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / metabolism
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / toxicity
  • Lewy Bodies / metabolism
  • Lysine / metabolism*
  • Mice
  • NIH 3T3 Cells
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotection* / drug effects
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Phenotype
  • Protein Aggregates*
  • Protein Binding / drug effects
  • Solubility
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination*

Substances

  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Protein Aggregates
  • Wsb1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lysine