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Neurobiol Dis. 2014 Oct;70:190-203. doi: 10.1016/j.nbd.2014.06.009. Epub 2014 Jun 24.

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

Author information

1
The Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USA. Electronic address: kdave@michaeljfox.org.
2
The Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USA.
3
Psychogenics, Inc. 765 Old Saw Mill River Road, Tarrytown, NY 10591 USA.
4
WIL Research 1407 George Road, Ashland, OH 44805 USA.
5
NeuroScience Associates. 10915 Lake Ridge Drive, Knoxville, TN 37934 USA.
6
Saint Louis University. 3437 Caroline, Suite 3113, St. Louis, MO 63104 USA.
7
Allen Institute for Brain Science 551N, 34th Street, Seattle, WA 98103 USA.
8
Leica Biosystems. 1360 Park Center Drive, Vista, CA 92081 USA.
9
SAGE Labs. 2033 Westport Center Drive, Saint Louis, MO, 63146 USA.
10
The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas TX 75390 USA.
11
BNRL, 1992 River Road, Morgantown, WV 26501 USA.

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 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.

PMID:
24969022
DOI:
10.1016/j.nbd.2014.06.009
[Indexed for MEDLINE]
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