A Drosophila model for LRRK2-linked parkinsonism.
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.
Liu
Zhaohui
Z
Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Wang
Xiaoyue
X
Yu
Yi
Y
Li
Xueping
X
Wang
Tao
T
Jiang
Haibing
H
Ren
Qiuting
Q
Jiao
Yuchen
Y
Sawa
Akira
A
Moran
Timothy
T
Ross
Christopher A
CA
Montell
Craig
C
Smith
Wanli W
WW
D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004296:Dopa Decarboxylase / Q000235:genetics / Q000378:metabolism; D004298:Dopamine / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D020233:Gait Disorders, Neurologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008854:Microscopy, Electron; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000378:metabolism
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D004296:Dopa Decarboxylase; D004298:Dopamine