Genetic and pharmacological evidence that G2019S LRRK2 confers a hyperkinetic phenotype, resistant to motor decline associated with aging

NEUROBIOLOGY OF DISEASE

卷:71

Article

Longo, Francesco^1,2  Russo, Isabella³  Shimshek, Derya R.⁴  Greggio, Elisa³  Morari, Michele^1,2 

[1] Univ Ferrara, Dept Med Sci, Pharmacol Sect, I-44121 Ferrara, Italy

[2] Univ Ferrara, Natl Inst Neurosci, I-44121 Ferrara, Italy

[3] Univ Padua, Dept Biol, I-35131 Padua, Italy

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

关键词: Aging;    D1994S knock-in;    G2019S knock-in;    H-1152;    LRRK2 kinase-dead;    LRRK2;    LRRK2 kinase inhibitors;    Nov-LRRK2-11;    Parkinson's disease;    Ser935 phosphorylation;   

DOI  :  10.1016/j.nbd.2014.07.013

来源: Elsevier

【 摘 要 】

The leucine-rich repeat kinase 2 mutation G2019S in the kinase-domain is the most common genetic cause of Parkinson's disease. To investigate the impact of the G2019S mutation on motor activity in vivo, a longitudinal phenotyping approach was developed in knock-in (KO mice bearing this kinase-enhancing mutation. Two cohorts of G2019S KI mice and wild-type littermates (WT) were subjected to behavioral tests, specific for aldnesia, bradykinesia and overall gait ability, at different ages (3, 6, 10, 15 and 19 months). The motor performance of G2019S KI mice remained stable up to the age of 19 months and did not show the typical age-related decline in immobility time and stepping activity of WT. Several lines of evidence suggest that enhanced LRRK2 kinase activity is the main contributor to the observed hyperkinetic phenotype of G2019S KI mice: i) KI mice carrying a LRRK2 kinase-dead mutation (D1994S KD) showed a similar progressive motor decline as WT; ii) two LRRK2 kinase inhibitors, H-1152 and Nov-LRRK2-11, acutely reversed the hyperkinetic phenotype of G2019S KI mice, while being ineffective in WT or D1994S KD animals. LRRK2 target engagement in vivo was further substantiated by reduction of LRRK2 phosphorylation at Ser935 in the striatum and cortex at efficacious doses of Nov-LRRK2-11, and in the striatum at efficacious doses of H-1152. In summary, expression of the G20195 mutation in the mouse LRRK2 gene confers a hyperkinetic phenotype that is resistant to age-related motor decline, likely via enhancement of LRRK2 kinase activity. This study provides an in vivo model to investigate the effects of LRRK2 inhibitors on motor function. (C) 2014 The Authors. Published by Elsevier inc.

【 授权许可】

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