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G2019S-LRRK2 mutation enhances MPTP-linked Parkinsonism in mice.
Arbez, Nicolas; He, XiaoFei; Huang, Yong; Ren, Mark; Liang, Yideng; Nucifora, Frederick C; Wang, Xiaofang; Pei, Zhong; Tessarolo, Lino; Smith, Wanli W; Ross, Christopher A.
Afiliación
  • Arbez N; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,Baltimore, MD 21287, USA.
  • He X; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,Baltimore, MD 21287, USA.
  • Huang Y; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,Baltimore, MD 21287, USA.
  • Ren M; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,Baltimore, MD 21287, USA.
  • Liang Y; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,Baltimore, MD 21287, USA.
  • Nucifora FC; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,Baltimore, MD 21287, USA.
  • Wang X; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,Baltimore, MD 21287, USA.
  • Pei Z; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,Baltimore, MD 21287, USA.
  • Tessarolo L; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA.
  • Smith WW; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,Baltimore, MD 21287, USA.
  • Ross CA; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine,Baltimore, MD 21287, USA.
Hum Mol Genet ; 29(4): 580-590, 2020 03 13.
Article en En | MEDLINE | ID: mdl-31813996
Parkinson's disease (PD) is a common neurodegenerative disease with a heterogeneous etiology that involves genetic and environmental factors or exogenous. Current LRRK2 PD animal models only partly reproduce the characteristics of the disease with very subtle dopaminergic neuron degeneration. We developed a new model of PD that combines a sub-toxic MPTP insult to the G2019S-LRRK2 mutation. Our newly generated mice, overexpressing mutant G2019S-LRRK2 protein in the brain, displayed a mild, age-dependent progressive motor impairment, but no reduction of lifespan. Cortical neurons from G2019S-LRRK2 mice showed an increased vulnerability to stress insults, compared with neurons overexpressing wild-type WT-LRRK2, or non-transgenic (nTg) neurons. The exposure of LRRK2 transgenic mice to a sub-toxic dose of MPTP resulted in severe motor impairment, selective loss of dopamine neurons and increased astrocyte activation, whereas nTg mice with MPTP exposure showed no deficits. Interestingly, mice overexpressing WT-LRRK2 showed a significant impairment that was milder than for the mutant G2019S-LRRK2 mice. L-DOPA treatments could partially improve the movement impairments but did not protect the dopamine neuron loss. In contrast, treatments with an LRRK2 kinase inhibitor significantly reduced the dopaminergic neuron degeneration in this interaction model. Our studies provide a novel LRRK2 gene-MPTP interaction PD mouse model, and a useful tool for future studies of PD pathogenesis and therapeutic intervention.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dopamina / Trastornos Parkinsonianos / Neuronas Dopaminérgicas / Trastornos Motores / Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina / Mutación Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dopamina / Trastornos Parkinsonianos / Neuronas Dopaminérgicas / Trastornos Motores / Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina / Mutación Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido