Unknown

Dataset Information

0

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


ABSTRACT: 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.

SUBMITTER: Yao C 

PROVIDER: S-EPMC2926296 | biostudies-other | 2010 Oct

REPOSITORIES: biostudies-other

altmetric image

Publications

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

Yao Chen C   El Khoury Rabih R   Wang Wen W   Byrd Tara A TA   Pehek Elizabeth A EA   Thacker Colin C   Zhu Xiongwei X   Smith Mark A MA   Wilson-Delfosse Amy L AL   Chen Shu G SG  

Neurobiology of disease 20100409 1


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 dop  ...[more]

Similar Datasets

| S-EPMC10227375 | biostudies-literature
2023-05-19 | GSE210005 | GEO
| S-EPMC3127548 | biostudies-literature
| S-EPMC3177653 | biostudies-literature
| S-EPMC4259338 | biostudies-literature
| S-EPMC4078806 | biostudies-other
| S-EPMC4455551 | biostudies-literature
| S-EPMC8026730 | biostudies-literature
| S-EPMC11354575 | biostudies-literature
| S-EPMC8415217 | biostudies-literature