Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases

Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson's disease (PD). G2019S, the most common amino acid substitution activates the kinase two- to threefold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2…

• NS
  National Science Foundation
• MJ
  Michael J. Fox Foundation for Parkinson's Research
• EL
  Eli Lilly and Company
• SN
  Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

  Award: P2ZHP3_151580
• M
  Max-Planck-Gesellschaft
• MF
  Max-Planck-Institut für Bildungsforschung
• NI
  National Institutes of Health
• MR
  Medical Research Council

  Award: MC_UU_12016/3