Deletion of the WD40 domain of LRRK2 in Zebrafish causes Parkinsonism-like loss of neurons and locomotive defect.
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.
Sheng
Donglai
D
Department of Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore.
Qu
Dianbo
D
Kwok
Ken Hon Hung
KH
Ng
Seok Shin
SS
Lim
Adrian Yin Ming
AY
Aw
Sharon Siqi
SS
Lee
Charlie Wah Heng
CW
Sung
Wing Kin
WK
Tan
Eng King
EK
Lufkin
Thomas
T
Jesuthasan
Suresh
S
Sinnakaruppan
Mathavan
M
Liu
Jianjun
J
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
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