Leucine-Rich Repeat Kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease

Hum Mol Genet. 2009 Nov 15;18(22):4390-404. doi: 10.1093/hmg/ddp394. Epub 2009 Aug 19.

Abstract

Mutations in the LRRK2 gene are the most common genetic cause of familial Parkinson's disease (PD). However, its physiological and pathological functions are unknown. Therefore, we generated several independent Drosophila lines carrying WT or mutant human LRRK2 (mutations in kinase, COR or LRR domains, resp.). Ectopic expression of WT or mutant LRRK2 in dopaminergic neurons caused their significant loss accompanied by complex age-dependent changes in locomotor activity. Overall, the ubiquitous expression of LRRK2 increased lifespan and fertility of the flies. However, these flies were more sensitive to rotenone. LRRK2 expression in the eye exacerbated retinal degeneration. Importantly, in double transgenic flies, various indices of the eye and dopaminergic survival were modified in a complex fashion by a concomitant expression of PINK1, DJ-1 or Parkin. This evidence suggests a genetic interaction between these PD-relevant genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / metabolism
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Life Expectancy
  • Male
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / physiopathology
  • Protein Binding
  • Protein Deglycase DJ-1
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Oncogene Proteins
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • PTEN-induced putative kinase
  • Protein Serine-Threonine Kinases
  • PARK7 protein, human
  • Protein Deglycase DJ-1