Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2014-10-01
|
| Series: | Neurobiology of Disease |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114001739 |
| _version_ | 1818676070730170368 |
|---|---|
| author | Kuldip D. Dave Shehan De Silva Niketa P. Sheth Sylvie Ramboz Melissa J. Beck Changyu Quang Robert C. Switzer, III Syed O. Ahmad Susan M. Sunkin Dan Walker Xiaoxia Cui Daniel A. Fisher Aaron M. McCoy Kevin Gamber Xiaodong Ding Matthew S. Goldberg Stanley A. Benkovic Meredith Haupt Marco A.S. Baptista Brian K. Fiske Todd B. Sherer Mark A. Frasier |
| author_facet | Kuldip D. Dave Shehan De Silva Niketa P. Sheth Sylvie Ramboz Melissa J. Beck Changyu Quang Robert C. Switzer, III Syed O. Ahmad Susan M. Sunkin Dan Walker Xiaoxia Cui Daniel A. Fisher Aaron M. McCoy Kevin Gamber Xiaodong Ding Matthew S. Goldberg Stanley A. Benkovic Meredith Haupt Marco A.S. Baptista Brian K. Fiske Todd B. Sherer Mark A. Frasier |
| author_sort | Kuldip D. Dave |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T08:37:38Z |
| format | Article |
| id | doaj.art-3b4ee316f83d4fc3bf43bea037f0fae8 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T08:37:38Z |
| publishDate | 2014-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-3b4ee316f83d4fc3bf43bea037f0fae82022-12-21T21:56:26ZengElsevierNeurobiology of Disease1095-953X2014-10-0170190203Phenotypic characterization of recessive gene knockout rat models of Parkinson's diseaseKuldip D. Dave0Shehan De Silva1Niketa P. Sheth2Sylvie Ramboz3Melissa J. Beck4Changyu Quang5Robert C. Switzer, III6Syed O. Ahmad7Susan M. Sunkin8Dan Walker9Xiaoxia Cui10Daniel A. Fisher11Aaron M. McCoy12Kevin Gamber13Xiaodong Ding14Matthew S. Goldberg15Stanley A. Benkovic16Meredith Haupt17Marco A.S. Baptista18Brian K. Fiske19Todd B. Sherer20Mark A. Frasier21The Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USA; Corresponding author.The Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USAThe Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USAPsychogenics, Inc. 765 Old Saw Mill River Road, Tarrytown, NY 10591 USAWIL Research 1407 George Road, Ashland, OH 44805 USAWIL Research 1407 George Road, Ashland, OH 44805 USANeuroScience Associates. 10915 Lake Ridge Drive, Knoxville, TN 37934 USASaint Louis University. 3437 Caroline, Suite 3113, St. Louis, MO 63104 USAAllen Institute for Brain Science 551 N, 34th Street, Seattle, WA 98103 USALeica Biosystems. 1360 Park Center Drive, Vista, CA 92081 USASAGE Labs. 2033 Westport Center Drive, Saint Louis, MO, 63146 USASAGE Labs. 2033 Westport Center Drive, Saint Louis, MO, 63146 USASAGE Labs. 2033 Westport Center Drive, Saint Louis, MO, 63146 USASAGE Labs. 2033 Westport Center Drive, Saint Louis, MO, 63146 USAThe University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas TX 75390 USAThe University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas TX 75390 USABNRL, 1992 River Road, Morgantown, WV 26501 USAThe Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USAThe Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USAThe Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USAThe Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USAThe Michael J. Fox Foundation for Parkinson's Research. 498 Seventh Avenue, 18th Floor, New York, NY 10018 USARecessively 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.http://www.sciencedirect.com/science/article/pii/S0969996114001739 |
| spellingShingle | Kuldip D. Dave Shehan De Silva Niketa P. Sheth Sylvie Ramboz Melissa J. Beck Changyu Quang Robert C. Switzer, III Syed O. Ahmad Susan M. Sunkin Dan Walker Xiaoxia Cui Daniel A. Fisher Aaron M. McCoy Kevin Gamber Xiaodong Ding Matthew S. Goldberg Stanley A. Benkovic Meredith Haupt Marco A.S. Baptista Brian K. Fiske Todd B. Sherer Mark A. Frasier Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease Neurobiology of Disease |
| title | Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease |
| title_full | Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease |
| title_fullStr | Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease |
| title_full_unstemmed | Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease |
| title_short | Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease |
| title_sort | phenotypic characterization of recessive gene knockout rat models of parkinson s disease |
| url | http://www.sciencedirect.com/science/article/pii/S0969996114001739 |
| work_keys_str_mv | AT kuldipddave phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT shehandesilva phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT niketapsheth phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT sylvieramboz phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT melissajbeck phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT changyuquang phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT robertcswitzeriii phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT syedoahmad phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT susanmsunkin phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT danwalker phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT xiaoxiacui phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT danielafisher phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT aaronmmccoy phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT kevingamber phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT xiaodongding phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT matthewsgoldberg phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT stanleyabenkovic phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT meredithhaupt phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT marcoasbaptista phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT briankfiske phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT toddbsherer phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease AT markafrasier phenotypiccharacterizationofrecessivegeneknockoutratmodelsofparkinsonsdisease |