A Drosophila model for LRRK2-linked parkinsonism

Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2693-8. doi: 10.1073/pnas.0708452105. Epub 2008 Feb 7.


Mutations in the leucine-rich repeat kinase (LRRK2) gene cause late-onset autosomal dominant Parkinson's disease (PD) with pleiomorphic pathology. Previously, we and others found that expression of mutant LRRK2 causes neuronal degeneration in cell culture. Here we used the GAL4/UAS system to generate transgenic Drosophila expressing either wild-type human LRRK2 or LRRK2-G2019S, the most common mutation associated with PD. Expression of either wild-type human LRRK2 or LRRK2-G2019S in the photoreceptor cells caused retinal degeneration. Expression of LRRK2 or LRRK2-G2019S in neurons produced adult-onset selective loss of dopaminergic neurons, locomotor dysfunction, and early mortality. Expression of mutant G2019S-LRRK2 caused a more severe parkinsonism-like phenotype than expression of equivalent levels of wild-type LRRK2. Treatment with l-DOPA improved mutant LRRK2-induced locomotor impairment but did not prevent the loss of tyrosine hydroxylase-positive neurons. To our knowledge, this is the first in vivo"gain-of-function" model which recapitulates several key features of LRRK2-linked human parkinsonism. These flies may provide a useful model for studying LRRK2-linked pathogenesis and for future therapeutic screens for PD intervention.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Dopa Decarboxylase / genetics
  • Dopa Decarboxylase / metabolism
  • Dopamine / genetics
  • Dopamine / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Drosophila melanogaster / ultrastructure
  • Gait Disorders, Neurologic / genetics
  • Gait Disorders, Neurologic / metabolism
  • Gait Disorders, Neurologic / pathology
  • Gene Expression Regulation
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Microscopy, Electron
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Parkinsonian Disorders / genetics
  • Parkinsonian Disorders / metabolism*
  • Parkinsonian Disorders / pathology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Retina / metabolism


  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases
  • Dopa Decarboxylase
  • Dopamine