RGD Reference Report - Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease. - Rat Genome Database

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Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease.

Authors: Dave, Kuldip D  De Silva, Shehan  Sheth, Niketa P  Ramboz, Sylvie  Beck, Melissa J  Quang, Changyu  Switzer, Robert C  Ahmad, Syed O  Sunkin, Susan M  Walker, Dan  Cui, Xiaoxia  Fisher, Daniel A  McCoy, Aaron M  Gamber, Kevin  Ding, Xiaodong  Goldberg, Matthew S  Benkovic, Stanley A  Haupt, Meredith  Baptista, Marco A S  Fiske, Brian K  Sherer, Todd B  Frasier, Mark A 
Citation: Dave KD, etal., Neurobiol Dis. 2014 Oct;70:190-203. doi: 10.1016/j.nbd.2014.06.009. Epub 2014 Jun 24.
RGD ID: 13210569
Pubmed: PMID:24969022   (View Abstract at PubMed)
DOI: DOI:10.1016/j.nbd.2014.06.009   (Journal Full-text)

Recessively inherited loss-of-function mutations in the PTEN-induced putative kinase 1(Pink1), DJ-1 (Park7) and Parkin (Park2) genes are linked to familial cases of early-onset Parkinson's disease (PD). As part of its strategy to provide more tools for the research community, The Michael J. Fox Foundation for Parkinson's Research (MJFF) funded the generation of novel rat models with targeted disruption ofPink1, DJ-1 or Parkin genes and determined if the loss of these proteins would result in a progressive PD-like phenotype. Pathological, neurochemical and behavioral outcome measures were collected at 4, 6 and 8months of age in homozygous KO rats and compared to wild-type (WT) rats. Both Pink1 and DJ-1 KO rats showed progressive nigral neurodegeneration with about 50% dopaminergic cell loss observed at 8 months of age. ThePink1 KO and DJ-1 KO rats also showed a two to three fold increase in striatal dopamine and serotonin content at 8 months of age. Both Pink1 KO and DJ-1 KO rats exhibited significant motor deficits starting at 4months of age. However, Parkin KO rats displayed normal behaviors with no neurochemical or pathological changes. These results demonstrate that inactivation of the Pink1 or DJ-1 genes in the rat produces progressive neurodegeneration and early behavioral deficits, suggesting that these recessive genes may be essential for the survival of dopaminergic neurons in the substantia nigra (SN). These MJFF-generated novel rat models will assist the research community to elucidate the mechanisms by which these recessive genes produce PD pathology and potentially aid in therapeutic development.



Disease Annotations    
Parkinsonism  (IMP,ISO)

Phenotype Annotations    
Objects Annotated

Genes (Rattus norvegicus)
Park7  (Parkinsonism associated deglycase)
Park7em1Sage  (parkinson protein 7; zinc finger nuclease induced mutant 1, Sigma Advanced Genetic Engineering Labs)
Pink1  (PTEN induced kinase 1)
Pink1em1Sage  (PTEN induced putative kinase 1; zinc finger nuclease induced mutant 1, Sigma Advanced Genetic Engineering Labs)

Genes (Mus musculus)
Park7  (Parkinson disease (autosomal recessive, early onset) 7)
Pink1  (PTEN induced putative kinase 1)

Genes (Homo sapiens)
PARK7  (Parkinsonism associated deglycase)
PINK1  (PTEN induced kinase 1)

Objects referenced in this article
Strain LE-Prknem1Sage-/- null Rattus norvegicus

Additional Information