Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease
<p>Abstract</p> <p>Background</p> <p>Huntington Disease (HD) is a neurodegenerative disorder in which caspase activation and cleavage of substrates, including the huntingtin protein, has been invoked as a pathological mechanism. Specific changes in caspase-2 (casp2) act...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2011-08-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://www.molecularneurodegeneration.com/content/6/1/59 |
| _version_ | 1811259819022090240 |
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| author | Bissada Nagat Deng Yu Zhang Wei-Ning Cao Li-Ping Ehrnhoefer Dagmar E Lerch Jason P Graham Rona K Southwell Amber L Carroll Jeffrey B Henkelman R Hayden Michael R |
| author_facet | Bissada Nagat Deng Yu Zhang Wei-Ning Cao Li-Ping Ehrnhoefer Dagmar E Lerch Jason P Graham Rona K Southwell Amber L Carroll Jeffrey B Henkelman R Hayden Michael R |
| author_sort | Bissada Nagat |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Huntington Disease (HD) is a neurodegenerative disorder in which caspase activation and cleavage of substrates, including the huntingtin protein, has been invoked as a pathological mechanism. Specific changes in caspase-2 (casp2) activity have been suggested to contribute to the pathogenesis of HD, however unique casp2 cleavage substrates have remained elusive. We thus utilized mice completely lacking casp2 (casp2-/-) to examine the role played by casp2 in the progression of HD. This 'substrate agnostic' approach allows us to query the effect of casp2 on HD progression without pre-defining proteolytic substrates of interest.</p> <p>Results</p> <p>YAC128 HD model mice lacking casp2 show protection from well-validated motor and cognitive features of HD, including performance on rotarod, swimming T-maze, pre-pulse inhibition, spontaneous alternation and locomotor tasks. However, the specific pathological features of the YAC128 mice including striatal volume loss and testicular degeneration are unaltered in mice lacking casp2. The application of high-resolution magnetic resonance imaging (MRI) techniques validates specific neuropathology in the YAC128 mice that is not altered by ablation of casp2.</p> <p>Conclusions</p> <p>The rescue of behavioral phenotypes in the absence of pathological improvement suggests that different pathways may be operative in the dysfunction of neural circuitry in HD leading to behavioral changes compared to the processes leading to cell death and volume loss. Inhibition of caspase-2 activity may be associated with symptomatic improvement in HD.</p> |
| first_indexed | 2024-04-12T18:37:22Z |
| format | Article |
| id | doaj.art-051163323b524f199342e91126fabc16 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-04-12T18:37:22Z |
| publishDate | 2011-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-051163323b524f199342e91126fabc162022-12-22T03:20:53ZengBMCMolecular Neurodegeneration1750-13262011-08-01615910.1186/1750-1326-6-59Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington diseaseBissada NagatDeng YuZhang Wei-NingCao Li-PingEhrnhoefer Dagmar ELerch Jason PGraham Rona KSouthwell Amber LCarroll Jeffrey BHenkelman RHayden Michael R<p>Abstract</p> <p>Background</p> <p>Huntington Disease (HD) is a neurodegenerative disorder in which caspase activation and cleavage of substrates, including the huntingtin protein, has been invoked as a pathological mechanism. Specific changes in caspase-2 (casp2) activity have been suggested to contribute to the pathogenesis of HD, however unique casp2 cleavage substrates have remained elusive. We thus utilized mice completely lacking casp2 (casp2-/-) to examine the role played by casp2 in the progression of HD. This 'substrate agnostic' approach allows us to query the effect of casp2 on HD progression without pre-defining proteolytic substrates of interest.</p> <p>Results</p> <p>YAC128 HD model mice lacking casp2 show protection from well-validated motor and cognitive features of HD, including performance on rotarod, swimming T-maze, pre-pulse inhibition, spontaneous alternation and locomotor tasks. However, the specific pathological features of the YAC128 mice including striatal volume loss and testicular degeneration are unaltered in mice lacking casp2. The application of high-resolution magnetic resonance imaging (MRI) techniques validates specific neuropathology in the YAC128 mice that is not altered by ablation of casp2.</p> <p>Conclusions</p> <p>The rescue of behavioral phenotypes in the absence of pathological improvement suggests that different pathways may be operative in the dysfunction of neural circuitry in HD leading to behavioral changes compared to the processes leading to cell death and volume loss. Inhibition of caspase-2 activity may be associated with symptomatic improvement in HD.</p>http://www.molecularneurodegeneration.com/content/6/1/59Huntington's Diseaseneurodegenerationcaspasemagnetic resonance imaging |
| spellingShingle | Bissada Nagat Deng Yu Zhang Wei-Ning Cao Li-Ping Ehrnhoefer Dagmar E Lerch Jason P Graham Rona K Southwell Amber L Carroll Jeffrey B Henkelman R Hayden Michael R Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease Molecular Neurodegeneration Huntington's Disease neurodegeneration caspase magnetic resonance imaging |
| title | Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease |
| title_full | Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease |
| title_fullStr | Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease |
| title_full_unstemmed | Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease |
| title_short | Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease |
| title_sort | mice lacking caspase 2 are protected from behavioral changes but not pathology in the yac128 model of huntington disease |
| topic | Huntington's Disease neurodegeneration caspase magnetic resonance imaging |
| url | http://www.molecularneurodegeneration.com/content/6/1/59 |
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