Elsevier

Neurobiology of Disease

Volume 70, October 2014, Pages 190-203
Neurobiology of Disease

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

https://doi.org/10.1016/j.nbd.2014.06.009Get rights and content
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Highlights

  • Creation of the first-ever Pink1 KO, DJ-1 KO and Parkin KO rat models of Parkinson's disease.

  • Detailed phenotypic characterization of these novel rat models at three ages.

  • Pink1 and DJ-1 KO rats display progressive motor deficits and gait dysfunction.

  • Pink1 and DJ-1 KO rats show a progressive loss of substantia nigra dopamine neurons.

  • Parkin KO rats display normal behavioral, neurochemical and pathological phenotype.

Abstract

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 8 months 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 4 months 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.

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