Combined LRRK2 mutation, aging and chronic low dose oral rotenone as a model of Parkinson's disease

Hui Fang Liu, Philip Wing Lok Ho, Gideon Chi Ting Leung, Colin Siu Chi Lam, Shirley Yin Yu Pang, Lingfei Li, Michelle Hiu Wai Kung, David Boyer Ramsden, Shu Leong Ho

Research output: Journal article publicationJournal articleAcademic researchpeer-review

37 Citations (Scopus)

Abstract

Aging, genetics and environmental toxicity are important etiological factors in Parkinson's disease (PD). However, its pathogenesis remains unclear. A major obstacle is the lack of an appropriate experimental model which incorporates genetic susceptibility, aging and prolonged environmental toxicity. Here, we explored the interplay amongst these factors using mutant LRRK2R1441G (leucine-rich-repeat-kinase-2) knockin mice. We found that mutant primary cortical and mesencephalic dopaminergic neurons were more susceptible to rotenone-induced ATP deficiency and cell death. Compared with wild-type controls, striatal synaptosomes isolated from young mutant mice exhibited significantly lower dopamine uptake after rotenone toxicity, due to reduced striatal synaptosomal mitochondria and synaptic vesicular proton pump protein (V-ATPase H) levels. Mutant mice developed greater locomotor deficits in open-field tests than wild-type mice following low oral rotenone doses given twice weekly over 50 weeks (half their lifespan). The increased locomotor deficit was associated with specific reduction in striatal mitochondrial Complex-I (NDUFS4) in rotenone-treated mutant but not in similarly treated wild-type mice. Our unique experimental model which incorporates genetic effect, natural aging and prolonged oral environmental toxicity administered to mutant knockin LRRK2 mice over half their life span, with observable and measurable phenotype, is invaluable in further studies of the pathogenic process and therapeutics of PD.

Original languageEnglish
Article number40887
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 18 Jan 2017
Externally publishedYes

ASJC Scopus subject areas

  • General

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