title: Deletion of the WD40 domain of LRRK2 in Zebrafish causes Parkinsonism-like loss of neurons and locomotive defect.
abstract: LRRK2 plays an important role in Parkinson's disease (PD), but its biological functions are largely unknown. Here, we cloned the homolog of human LRRK2, characterized its expression, and investigated its biological functions in zebrafish. The blockage of zebrafish LRRK2 (zLRRK2) protein by morpholinos caused embryonic lethality and severe developmental defects such as growth retardation and loss of neurons. In contrast, the deletion of the WD40 domain of zLRRK2 by morpholinos targeting splicing did not induce severe embryonic developmental defects; rather it caused Parkinsonism-like phenotypes, including loss of dopaminergic neurons in diencephalon and locomotion defects. These neurodegenerative and locomotion defects could be rescued by over-expressing zLRRK2 or hLRRK2 mRNA. The administration of L-dopa could also rescue the locomotion defects, but not the neurodegeneration. Taken together, our results demonstrate that zLRRK2 is an ortholog of hLRRK2 and that the deletion of WD40 domain of zLRRK2 provides a disease model for PD.
authors.affiliation: Department of Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore.
authors.forename: Donglai
authors.initials: D
authors.lastname: Sheng
authors.forename: Dianbo
authors.initials: D
authors.lastname: Qu
authors.forename: Ken Hon Hung
authors.initials: KH
authors.lastname: Kwok
authors.forename: Seok Shin
authors.initials: SS
authors.lastname: Ng
authors.forename: Adrian Yin Ming
authors.initials: AY
authors.lastname: Lim
authors.forename: Sharon Siqi
authors.initials: SS
authors.lastname: Aw
authors.forename: Charlie Wah Heng
authors.initials: CW
authors.lastname: Lee
authors.forename: Wing Kin
authors.initials: WK
authors.lastname: Sung
authors.forename: Eng King
authors.initials: EK
authors.lastname: Tan
authors.forename: Thomas
authors.initials: T
authors.lastname: Lufkin
authors.forename: Suresh
authors.initials: S
authors.lastname: Jesuthasan
authors.forename: Mathavan
authors.initials: M
authors.lastname: Sinnakaruppan
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D015027:Zebrafish / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D029961:Zebrafish Proteins; C495280:LRRK2 protein, human; C551314:LRRK2 protein, zebrafish; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases