LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson's disease

NEUROBIOLOGY OF DISEASE

卷:40

Article

Yao, Chen²  El Khoury, Rabih²  Wang, Wen²  Byrd, Tara A.³  Pehek, Elizabeth A.^3,4  Thacker, Colin⁵  Zhu, Xiongwei²  Smith, Mark A.²  Wilson-Delfosse, Amy L.¹  Chen, Shu G.² 

[1] Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA

[2] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA

[3] Louis Stokes Cleveland Dept Vet Affairs, Cleveland, OH 44106 USA

[4] Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA

[5] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA

关键词: Leucine-rich repeat kinase 2;    Parkinson's disease;    Caenorhabditis elegans;    Dopamine;    Neurodegeneration;   

DOI  :  10.1016/j.nbd.2010.04.002

来源: Elsevier

【 摘 要 】

Mutations in LRRK2 are thus far the most frequent known cause of autosomal dominant and idiopathic Parkinson's disease (PD) with prevalent mutations being found within the GTPase (R1441C/G) and kinase (G20195) domains. Previous in vitro studies have revealed that R1441C and G2019S mutations are associated with increased kinase activity. To better understand LRRK2-linked PD pathogenesis in vivo, we have generated transgenic C. elegans overexpressing human LRRK2 wild type, R1441C and G2019S in dopaminergic (DA) neurons. Overexpression of these LRRK2 proteins causes age-dependent DA neurodegeneration, behavioral deficits, and locomotor dysfunction that are accompanied by a reduction of dopamine levels in vivo. In comparison, R1441C and G20195 mutants cause more severe phenotypes than the wild type protein. Interestingly, treatment with exogenous dopamine rescues the LRRK2-induced behavioral and locomotor phenotypes. In contrast, expression of the GTP binding defective mutant. K1347A, or knockout of the C. elegans LRRK2 homolog, LRK-1, prevents the LRRK2-induced neurodegeneration and behavioral abnormalities. Hence, our transgenic LRRK2 C. elegans models recapitulate key features of PD including progressive neurodegeneration, impairment of dopamine-dependent behavior and locomotor function, and reduction in dopamine levels. Furthermore, our findings provide strong support for the critical role of GTPase/kinase activity in LRRK2-linked pathologies. These invertebrate models will be useful for studying pathogenesis of PD and for development of potential therapeutics for the disease. (C) 2010 Elsevier Inc. All rights reserved.

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