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.

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

“…Transgenic overexpression of human I2020T LRRK2 in Drosophila also induces DA neuron degeneration by a mechanism that is proposed to involve phosphorylation of 4E-BP [75], although this mechanism is controversial [72,119]. Overexpression of human LRRK2 in Caenorhabditis elegans also mediate age-dependent DA neurodegeneration, reduction of dopamine levels in vivo, behavioral deficits, and locomotor dysfunction that is more profound for G2019S than wild-type protein [120,121]. Transgenic expression of human R1441C mutant LRRK2 in C. elegans induces age-dependent DA neurodegeneration and locomotor deficit accompanied by a reduction in dopamine levels [120].…”

“…Overexpression of human LRRK2 in Caenorhabditis elegans also mediate age-dependent DA neurodegeneration, reduction of dopamine levels in vivo, behavioral deficits, and locomotor dysfunction that is more profound for G2019S than wild-type protein [120,121]. Transgenic expression of human R1441C mutant LRRK2 in C. elegans induces age-dependent DA neurodegeneration and locomotor deficit accompanied by a reduction in dopamine levels [120]. In Drosophila, a dLRRK Y1383C mutant (analogous to human Y1699C) caused prominent vesicular aggregation of the protein and DA neuron loss [75].…”

The role of α-synuclein in neurodegeneration — An update

“…MPTP [738], rotenone and paraquat [739][740][741][742], and genetic. Despite [748][749][750], Caenorhabditis elegans [492,751] and in mammalians [752] have been developed to study the cellular mechanisms impaired in this disease [746].…”

Modeling LRRK2 Parkinsonism

“…Additionally, the increased sensitivity of LRK-1 loss-of-function worms to tunicamycin was reduced in PINK-1 loss-of-function mutants, suggesting an antagonistic role of PINK-1 and LRK-1 (Samann et al, 2009). Curiously, loss of LRK-1 also attenuates transgenic LRRK2-induced DA neurodegeneration and basal slowing behavioral phenotype (Yao et al, 2010) …”