التفاصيل البيبلوغرافية
| العنوان: |
LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson's disease |
| المؤلفون: |
Chen Yao, Rabih El Khoury, Wen Wang, Tara A. Byrd, Elizabeth A. Pehek, Colin Thacker, Xiongwei Zhu, Mark A. Smith, Amy L. Wilson-Delfosse, Shu G. Chen |
| المصدر: |
Neurobiology of Disease, Vol 40, Iss 1, Pp 73-81 (2010) |
| بيانات النشر: |
Elsevier, 2010. |
| سنة النشر: |
2010 |
| المجموعة: |
LCC:Neurosciences. Biological psychiatry. Neuropsychiatry |
| مصطلحات موضوعية: |
Leucine-rich repeat kinase 2, Parkinson's disease, Caenorhabditis elegans, Dopamine, Neurodegeneration, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571 |
| الوصف: |
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 (G2019S) 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 G2019S 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. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
1095-953X |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S0969996110000999; https://doaj.org/toc/1095-953X |
| DOI: |
10.1016/j.nbd.2010.04.002 |
| URL الوصول: |
https://doaj.org/article/973a9d85193c4136af315df55f2f93ea |
| رقم الانضمام: |
edsdoj.973a9d85193c4136af315df55f2f93ea |
| قاعدة البيانات: |
Directory of Open Access Journals |