The Parkinson's disease-linked Leucine-rich repeat kinase 2 (LRRK2) is required for insulin-stimulated translocation of GLUT4

Sci Rep. 2019 Mar 14;9(1):4515. doi: 10.1038/s41598-019-40808-y.


Mutations within Leucine-rich repeat kinase 2 (LRRK2) are associated with late-onset Parkinson's disease. The physiological function of LRRK2 and molecular mechanism underlying the pathogenic role of LRRK2 mutations remain uncertain. Here, we investigated the role of LRRK2 in intracellular signal transduction. We find that deficiency of Lrrk2 in rodents affects insulin-dependent translocation of glucose transporter type 4 (GLUT4). This deficit is restored during aging by prolonged insulin-dependent activation of protein kinase B (PKB, Akt) and Akt substrate of 160 kDa (AS160), and is compensated by elevated basal expression of GLUT4 on the cell surface. Furthermore, we find a crucial role of Rab10 phosphorylation by LRRK2 for efficient insulin signal transduction. Translating our findings into human cell lines, we find comparable molecular alterations in fibroblasts from Parkinson's patients with the known pathogenic G2019S LRRK2 mutation. Our results highlight the role of LRRK2 in insulin-dependent signalling with potential therapeutic implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Fibroblast Growth Factors / pharmacology
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Glucose Transporter Type 4 / metabolism*
  • Humans
  • Insulin / pharmacology*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
  • Mice
  • Neuronal Outgrowth / drug effects
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology*
  • Phosphorylation
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Signal Transduction / drug effects*
  • rab GTP-Binding Proteins / metabolism


  • Glucose Transporter Type 4
  • Insulin
  • Rab10 protein, rat
  • Fibroblast Growth Factors
  • LRRK2 protein, rat
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Proto-Oncogene Proteins c-akt
  • rab GTP-Binding Proteins