A Drosophila model for LRRK2-linked parkinsonism

Zhaohui Liu, Xiaoyue Wang, Yi Yu, Xueping Li, Tao Wang, Haibing Jiang, Qiuting Ren, Yuchen Jiao, Akira Sawa, Timothy Moran, Christopher A. Ross, Craig Montell, Wanli W. Smith

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2693-2698
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number7
DOIs
StatePublished - Feb 19 2008

Keywords

  • Dopaminergic neuron
  • Parkinson's disease

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'A Drosophila model for LRRK2-linked parkinsonism'. Together they form a unique fingerprint.

Cite this