G2019S LRRK2 mutation facilitates α-synuclein neuropathology in aged mice

NEUROBIOLOGY OF DISEASE

卷:120

Article

Novello, Salvatore¹  Arcuri, Ludovico¹  Dovero, Sandra^2,3  Dutheil, Nathalie^2,3  Shimshek, Derya R.⁴  Bezard, Erwan^2,3  Morari, Michele¹ 

[1] Univ Ferrara, Natl Inst Neurosci, Sect Pharmacol, Dept Med Sci, Ferrara, Italy

[2] Univ Bordeaux, Inst Malad Neurodegenerat, UMR 5293, F-33000 Bordeaux, France

[3] CNRS, Inst Malad Neurodegenerat, UMR 5293, F-33000 Bordeaux, France

[4] Novartis Pharma AG, Novartis Inst BioMed Res, Dept Neurosci, CH-4002 Basel, Switzerland

关键词: alpha-synuclein;    G2019S knock-in mice;    iba-1;    LRRK2;    Microglia;    Parkinson's disease;   

DOI  :  10.1016/j.nbd.2018.08.018

来源: Elsevier

【 摘 要 】

Fibrillization of alpha-synuclein is instrumental for the development of Parkinson's disease (PD), thus modulating this process can have profound impact on disease initiation/progression. Here, the impact of the p.G2019S mutation of leucine-rich repeat kinase 2 (LRRK2), which is most frequently associated with familial and sporadic PD, on alpha-synuclein pathology was investigated. G2019S knock-in mice and wild-type controls were injected with a recombinant adeno-associated viral vector serotype 2/9 (AAV2/9) overexpressing human mutant p.A53T alpha-asynuclein (AAV2/9-h alpha-syn). Control animals were injected with AAV2/9 carrying green fluorescent protein. Motor behavior, transgene expression, alpha-syn and pSer129 alpha-syn load, number of nigral dopamine neurons and density of striatal dopaminergic terminals were evaluated. To investigate the effect of aging, experiments were performed in 3- and 12-month-old mice, evaluated 20 and 12 weeks after virus injection, respectively. h alpha-syn overexpression induced progressive motor deficits, loss of nigral dopaminergic neurons and striatal terminals, and appearance of proteinase K-resistant aggregates of pSer129 alpha-syn in both young and old mice. Although no genotype difference was observed in 3-month-old mice, degeneration of nigral dopaminergic neurons was higher in 12-month-old G2019S knock-in mice compared with age-matched wild-type controls ( - 55% vs - 39%, respectively). Consistently, a two-fold higher load of pSer129 alpha-syn aggregates was found in 12-month-old G2019S knock-in mice. We conclude that G2019S LRRK2 facilitates alpha-synucleinopathy and degeneration of nigral dopaminergic neurons, and that aging is a major determinant of this effect.

【 授权许可】

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