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


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.

SUBMITTER: Liu HF 

PROVIDER: S-EPMC5241661 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Liu Hui-Fang HF   Ho Philip Wing-Lok PW   Leung Gideon Chi-Ting GC   Lam Colin Siu-Chi CS   Pang Shirley Yin-Yu SY   Li Lingfei L   Kung Michelle Hiu-Wai MH   Ramsden David Boyer DB   Ho Shu-Leong SL  

Scientific reports 20170118


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 LRRK2<sup>R1441G</sup> (leucine-rich-repeat-kinase-2) knockin mice. We found that mutant primary cortical and mesencephalic dopamin  ...[more]

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