Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila

Biochem Biophys Res Commun. 2007 Jun 29;358(2):534-9. doi: 10.1016/j.bbrc.2007.04.156. Epub 2007 May 4.

Abstract

Mutations in LRRK2/PARK8 are linked to autosomal dominant forms of Parkinson's disease, but the pathogenic mechanism of LRRK2-associated Parkinson's disease is not fully understood. Moreover, in vivo functions of LRRK2 have not been addressed so far. Thus, we generated and characterized transgenic animals and loss-of-function mutants for LRRK, a sole Drosophila orthologue of human LRRK2. While transgenic expression of pathogenic mutant and wild type LRRK did not show any significant defects, LRRK loss-of-function mutants exhibited severely impaired locomotive activity. Moreover, dopaminergic neurons in LRRK mutants showed a severe reduction in tyrosine hydroxylase immunostaining and shrunken morphology, implicating their degeneration in the mutants. Collectively, our findings unprecedentedly show in vivo that LRRK2 is critical for the integrity of dopaminergic neurons and intact locomotive activity in Drosophila.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Cells, Cultured
  • Dopamine / metabolism
  • Drosophila / genetics
  • Drosophila / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology*
  • Neurons / metabolism*
  • Neurons / pathology*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, Dopamine / metabolism*

Substances

  • Drosophila Proteins
  • Receptors, Dopamine
  • LRRK protein, Drosophila
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases
  • Dopamine