PUBLICATION
Deletion of the WD40 domain of LRRK2 in Zebrafish causes Parkinsonism-like loss of neurons and locomotive defect
- Authors
- Sheng, D., Qu, D., Kwok, K.H., Ng, S.S., Lim, A.Y., Aw, S.S., Lee, C.W., Sung, W.K., Tan, E.K., Lufkin, T., Jesuthasan, S., Sinnakaruppan, M., and Liu, J.
- ID
- ZDB-PUB-100504-5
- Date
- 2010
- Source
- PLoS Genetics 6(4): e1000914 (Journal)
- Registered Authors
- Jesuthasan, Suresh
- Keywords
- Zebrafish, Neurons, Morpholino, Parkinson disease, Biological locomotion, Developmental neuroscience, Neuronal morphology, Complementary DNA
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Disease Models, Animal
- Embryo, Nonmammalian/metabolism
- Humans
- Mutation
- Nerve Degeneration/genetics
- Neurons/metabolism*
- Parkinsonian Disorders/genetics*
- Parkinsonian Disorders/metabolism
- Protein Serine-Threonine Kinases/genetics*
- Protein Serine-Threonine Kinases/metabolism
- Protein Structure, Tertiary
- Sequence Deletion*
- Zebrafish/genetics*
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 20421934 Full text @ PLoS Genet.
Citation
Sheng, D., Qu, D., Kwok, K.H., Ng, S.S., Lim, A.Y., Aw, S.S., Lee, C.W., Sung, W.K., Tan, E.K., Lufkin, T., Jesuthasan, S., Sinnakaruppan, M., and Liu, J. (2010) Deletion of the WD40 domain of LRRK2 in Zebrafish causes Parkinsonism-like loss of neurons and locomotive defect. PLoS Genetics. 6(4):e1000914.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping