title: Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease.
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.
authors: The Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USA. Electronic address: kdave@michaeljfox.org.
authors: Kuldip D
authors: KD
authors: Dave
authors: The Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USA.
authors: Shehan
authors: S
authors: De Silva
authors: The Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USA.
authors: Niketa P
authors: NP
authors: Sheth
authors: Psychogenics, Inc. 765 Old Saw Mill River Road, Tarrytown, NY 10591 USA.
authors: Sylvie
authors: S
authors: Ramboz
authors: WIL Research 1407 George Road, Ashland, OH 44805 USA.
authors: Melissa J
authors: MJ
authors: Beck
authors: WIL Research 1407 George Road, Ashland, OH 44805 USA.
authors: Changyu
authors: C
authors: Quang
authors: NeuroScience Associates. 10915 Lake Ridge Drive, Knoxville, TN 37934 USA.
authors: Robert C
authors: RC
authors: Switzer
authors: Saint Louis University. 3437 Caroline, Suite 3113, St. Louis, MO 63104 USA.
authors: Syed O
authors: SO
authors: Ahmad
authors: Allen Institute for Brain Science 551N, 34th Street, Seattle, WA 98103 USA.
authors: Susan M
authors: SM
authors: Sunkin
authors: Leica Biosystems. 1360 Park Center Drive, Vista, CA 92081 USA.
authors: Dan
authors: D
authors: Walker
authors: SAGE Labs. 2033 Westport Center Drive, Saint Louis, MO, 63146 USA.
authors: Xiaoxia
authors: X
authors: Cui
authors: SAGE Labs. 2033 Westport Center Drive, Saint Louis, MO, 63146 USA.
authors: Daniel A
authors: DA
authors: Fisher
authors: SAGE Labs. 2033 Westport Center Drive, Saint Louis, MO, 63146 USA.
authors: Aaron M
authors: AM
authors: McCoy
authors: SAGE Labs. 2033 Westport Center Drive, Saint Louis, MO, 63146 USA.
authors: Kevin
authors: K
authors: Gamber
authors: The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas TX 75390 USA.
authors: Xiaodong
authors: X
authors: Ding
authors: The University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas TX 75390 USA.
authors: Matthew S
authors: MS
authors: Goldberg
authors: BNRL, 1992 River Road, Morgantown, WV 26501 USA.
authors: Stanley A
authors: SA
authors: Benkovic
authors: The Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USA.
authors: Meredith
authors: M
authors: Haupt
authors: The Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USA.
authors: Marco A S
authors: MA
authors: Baptista
authors: The Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USA.
authors: Brian K
authors: BK
authors: Fiske
authors: The Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USA.
authors: Todd B
authors: TB
authors: Sherer
authors: The Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USA.
authors: Mark A
authors: MA
authors: Frasier
mesh_terms: D000375:Aging; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000473:pathology / Q000502:physiology; D055786:Gene Knockout Techniques; D005808:Genes, Recessive; D008297:Male; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000235:genetics; D009043:Motor Activity / Q000502:physiology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D010641:Phenotype; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics; D020318:Rats, Long-Evans; D012701:Serotonin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004298:Dopamine; D008869:Microtubule-Associated Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D012701:Serotonin; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C404267:PARK7 protein, rat