Insights into the cellular consequences of LRRK2-mediated Rab protein phosphorylation

Biochem Soc Trans. 2023 Apr 26;51(2):587-595. doi: 10.1042/BST20201145.

Abstract

Point mutations in leucine-rich repeat kinase 2 (LRRK2) which cause Parkinson's disease increase its kinase activity, and a subset of Rab GTPases have been identified as endogenous LRRK2 kinase substrates. Their phosphorylation correlates with a loss-of-function for the membrane trafficking steps they are normally involved in, but it also allows them to bind to a novel set of effector proteins with dominant cellular consequences. In this brief review, we will summarize novel findings related to the LRRK2-mediated phosphorylation of Rab GTPases and its various cellular consequences in vitro and in the intact brain, and we will highlight major outstanding questions in the field.

Keywords: LRRK2; Parkinson's disease; Rab protein; ciliogenesis; lysosome; phosphorylation/dephosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / metabolism
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism
  • Phosphorylation
  • rab GTP-Binding Proteins* / metabolism

Substances

  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • LRRK2 protein, human
  • rab GTP-Binding Proteins