| Effects of partial suppression of parkin on huntingtin mutant R6/1 mice. | |
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MedLine Citation:
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PMID: 19464273 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Huntington's disease (HD) is a neurodegenerative disorder caused by an expansion of polyglutamines which makes huntingtin more resistant to degradation. Parkin is an ubiquitin ligase which promotes proteosomal degradation of abnormal proteins. We investigated whether partial suppression of parkin increases HD phenotype. We studied the behavior and brain histology and biochemistry of the mice produced by interbreeding of R6/1 (model of HD in mice) with Park-2(-/-) (parkin null mice): R6/1, WT (wild-type), PK(+/-) (hemizygotic deletion of Park-2) and R6/1/PK(+/-). R6/1 and R6/1/PK(+/-) mice had abnormal motor and exploratory behavior. R6/1/PK(+/-) mice were more akinetic. These two groups of mice had severe but similar loss of nigrostriatal dopamine neurons and monoamine levels in striatum. R6/1/PK(+/-) mice had fewer huntingtin inclusions and a greater number of TUNEL(+) cells than R6/1 in striatum but there were no differences in the hippocampus. DARPP-32 protein was equally reduced in striatum of R6/1 and R6/1/PK(+/-) mice. Striatal levels of GSH were increased, of HSP-70 reduced and of CHIP unchanged in both R6/1 and R6/1/PK(+/-) mice. LC-3 II/I ratios were significantly increased in striatum of R6/1/PK(+/-) mice. Partial suppression of parkin slightly aggravates the phenotype in R6/1 mice, confirming a pathogenic role of the UPS in the processing of mutant huntingtin. The absence of massive additional cellular lesions in R6/1/PK(+/-) mice suggests the existence of compensatory mechanisms, such as autophagy, for the processing of huntingtin. |
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Authors:
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Isabel Rubio; José Antonio Rodríguez-Navarro; Cristina Tomás-Zapico; Carolina Ruíz; María José Casarejos; Juan Perucho; Ana Gómez; Izaskun Rodal; José J Lucas; María Angeles Mena; Justo García de Yébenes |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-05-21 |
Journal Detail:
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Title: Brain research Volume: 1281 ISSN: 1872-6240 ISO Abbreviation: Brain Res. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-07-06 Completed Date: 2009-09-30 Revised Date: 2012-07-11 |
Medline Journal Info:
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Nlm Unique ID: 0045503 Medline TA: Brain Res Country: Netherlands |
Other Details:
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Languages: eng Pagination: 91-100 Citation Subset: IM |
Affiliation:
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Servicio de Neurología, Hospital Ramón y Cajal, Madrid, Spain. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biogenic Monoamines / metabolism Brain / metabolism, pathology* Cell Death / genetics Disease Models, Animal Dopamine / metabolism Exploratory Behavior* HSP70 Heat-Shock Proteins / metabolism Humans Huntington Disease / genetics*, physiopathology Male Mice Mice, Knockout Mice, Mutant Strains Microtubule-Associated Proteins / metabolism Motor Activity / genetics* Nerve Tissue Proteins / genetics Neurons / drug effects, pathology Nuclear Proteins / genetics Phenotype Ubiquitin-Protein Ligases / genetics*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Biogenic Monoamines; 0/HSP70 Heat-Shock Proteins; 0/HTT protein, human; 0/MAP1LC3 protein, mouse; 0/Microtubule-Associated Proteins; 0/Nerve Tissue Proteins; 0/Nuclear Proteins; EC 6.3.2.19/CHIP protein, mouse; EC 6.3.2.19/Ubiquitin-Protein Ligases; EC 6.3.2.19/parkin protein |
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