title: 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.
authors.affiliation: Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.forename: Rabih
authors.initials: R
authors.lastname: El Khoury
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.forename: Tara A
authors.initials: TA
authors.lastname: Byrd
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Pehek
authors.forename: Colin
authors.initials: C
authors.lastname: Thacker
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Amy L
authors.initials: AL
authors.lastname: Wilson-Delfosse
authors.forename: Shu G
authors.initials: SG
authors.lastname: Chen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009422:Nervous System Diseases / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism* / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine
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