Inhibition of Polyglutamine Aggregation in R6/2 HD Brain Slices—Complex Dose–Response Profiles
Huntington's disease (HD) is a late onset neurodegenerative disorder caused by a CAG/polyglutamine (polyQ) repeat expansion. PolyQ aggregates can be detected in the nuclei and processes of neurons in HD patients and mouse models prior to the onset of symptoms. The misfolding and aggregation pat...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2001-12-01
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| Series: | Neurobiology of Disease |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996101904383 |
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doaj-fa08d20b29484b8d8f8a3bbfc905b226 |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Donna L. Smith Ruben Portier Ben Woodman Emma Hockly Amarbirpal Mahal William E. Klunk Xiao-Jiang Li Erich Wanker Karl D. Murray Gillian P. Bates |
| spellingShingle |
Donna L. Smith Ruben Portier Ben Woodman Emma Hockly Amarbirpal Mahal William E. Klunk Xiao-Jiang Li Erich Wanker Karl D. Murray Gillian P. Bates Inhibition of Polyglutamine Aggregation in R6/2 HD Brain Slices—Complex Dose–Response Profiles Neurobiology of Disease |
| author_facet |
Donna L. Smith Ruben Portier Ben Woodman Emma Hockly Amarbirpal Mahal William E. Klunk Xiao-Jiang Li Erich Wanker Karl D. Murray Gillian P. Bates |
| author_sort |
Donna L. Smith |
| title |
Inhibition of Polyglutamine Aggregation in R6/2 HD Brain Slices—Complex Dose–Response Profiles |
| title_short |
Inhibition of Polyglutamine Aggregation in R6/2 HD Brain Slices—Complex Dose–Response Profiles |
| title_full |
Inhibition of Polyglutamine Aggregation in R6/2 HD Brain Slices—Complex Dose–Response Profiles |
| title_fullStr |
Inhibition of Polyglutamine Aggregation in R6/2 HD Brain Slices—Complex Dose–Response Profiles |
| title_full_unstemmed |
Inhibition of Polyglutamine Aggregation in R6/2 HD Brain Slices—Complex Dose–Response Profiles |
| title_sort |
inhibition of polyglutamine aggregation in r6/2 hd brain slices—complex dose–response profiles |
| publisher |
Elsevier |
| series |
Neurobiology of Disease |
| issn |
1095-953X |
| publishDate |
2001-12-01 |
| description |
Huntington's disease (HD) is a late onset neurodegenerative disorder caused by a CAG/polyglutamine (polyQ) repeat expansion. PolyQ aggregates can be detected in the nuclei and processes of neurons in HD patients and mouse models prior to the onset of symptoms. The misfolding and aggregation pathway is an important therapeutic target. To better test the efficacy of aggregation inhibitors, we have developed an organotypic slice culture system. We show here that the formation of polyQ aggregates in hippocampal slices established from the R6/2 mouse follows the same prescribed sequence as occurs in vivo. Using this assay, we show that Congo red and chrysamine G can modulate aggregate formation, but show complex dose–response curves. Oral administration of creatine has been shown to delay the onset of all aspects of the phenotype and neuropathology in R6/2 mice. We show here that creatine can similarly inhibit aggregate formation in the slice culture assay. |
| url |
http://www.sciencedirect.com/science/article/pii/S0969996101904383 |
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doaj-fa08d20b29484b8d8f8a3bbfc905b2262021-03-20T04:47:20ZengElsevierNeurobiology of Disease1095-953X2001-12-018610171026Inhibition of Polyglutamine Aggregation in R6/2 HD Brain Slices—Complex Dose–Response ProfilesDonna L. Smith0Ruben Portier1Ben Woodman2Emma Hockly3Amarbirpal Mahal4William E. Klunk5Xiao-Jiang Li6Erich Wanker7Karl D. Murray8Gillian P. Bates9Division of Medical and Molecular Genetics, GKT School of Medicine, King's College, London, United Kingdom; Department of Neurology, Faculty of Medicine, Academic Hospital Nijmegen, The Netherlands; Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, 15261; Department of Genetics, Emory University, Atlanta, Georgia, 30322; Max-Planck Institut für Molekulare Genetik, Ihnestrasse 73, D-14195, Berlin, Germany; University of California,-Davis, Center for Neuroscience, 1544 Newton Court, Davis, California, 95616Division of Medical and Molecular Genetics, GKT School of Medicine, King's College, London, United Kingdom; Department of Neurology, Faculty of Medicine, Academic Hospital Nijmegen, The Netherlands; Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, 15261; Department of Genetics, Emory University, Atlanta, Georgia, 30322; Max-Planck Institut für Molekulare Genetik, Ihnestrasse 73, D-14195, Berlin, Germany; University of California,-Davis, Center for Neuroscience, 1544 Newton Court, Davis, California, 95616Division of Medical and Molecular Genetics, GKT School of Medicine, King's College, London, United Kingdom; Department of Neurology, Faculty of Medicine, Academic Hospital Nijmegen, The Netherlands; Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, 15261; Department of Genetics, Emory University, Atlanta, Georgia, 30322; Max-Planck Institut für Molekulare Genetik, Ihnestrasse 73, D-14195, Berlin, Germany; University of California,-Davis, Center for Neuroscience, 1544 Newton Court, Davis, California, 95616Division of Medical and Molecular Genetics, GKT School of Medicine, King's College, London, United Kingdom; Department of Neurology, Faculty of Medicine, Academic Hospital Nijmegen, The Netherlands; Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, 15261; Department of Genetics, Emory University, Atlanta, Georgia, 30322; Max-Planck Institut für Molekulare Genetik, Ihnestrasse 73, D-14195, Berlin, Germany; University of California,-Davis, Center for Neuroscience, 1544 Newton Court, Davis, California, 95616Division of Medical and Molecular Genetics, GKT School of Medicine, King's College, London, United Kingdom; Department of Neurology, Faculty of Medicine, Academic Hospital Nijmegen, The Netherlands; Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, 15261; Department of Genetics, Emory University, Atlanta, Georgia, 30322; Max-Planck Institut für Molekulare Genetik, Ihnestrasse 73, D-14195, Berlin, Germany; University of California,-Davis, Center for Neuroscience, 1544 Newton Court, Davis, California, 95616Division of Medical and Molecular Genetics, GKT School of Medicine, King's College, London, United Kingdom; Department of Neurology, Faculty of Medicine, Academic Hospital Nijmegen, The Netherlands; Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, 15261; Department of Genetics, Emory University, Atlanta, Georgia, 30322; Max-Planck Institut für Molekulare Genetik, Ihnestrasse 73, D-14195, Berlin, Germany; University of California,-Davis, Center for Neuroscience, 1544 Newton Court, Davis, California, 95616Division of Medical and Molecular Genetics, GKT School of Medicine, King's College, London, United Kingdom; Department of Neurology, Faculty of Medicine, Academic Hospital Nijmegen, The Netherlands; Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, 15261; Department of Genetics, Emory University, Atlanta, Georgia, 30322; Max-Planck Institut für Molekulare Genetik, Ihnestrasse 73, D-14195, Berlin, Germany; University of California,-Davis, Center for Neuroscience, 1544 Newton Court, Davis, California, 95616Division of Medical and Molecular Genetics, GKT School of Medicine, King's College, London, United Kingdom; Department of Neurology, Faculty of Medicine, Academic Hospital Nijmegen, The Netherlands; Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, 15261; Department of Genetics, Emory University, Atlanta, Georgia, 30322; Max-Planck Institut für Molekulare Genetik, Ihnestrasse 73, D-14195, Berlin, Germany; University of California,-Davis, Center for Neuroscience, 1544 Newton Court, Davis, California, 95616Division of Medical and Molecular Genetics, GKT School of Medicine, King's College, London, United Kingdom; Department of Neurology, Faculty of Medicine, Academic Hospital Nijmegen, The Netherlands; Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, 15261; Department of Genetics, Emory University, Atlanta, Georgia, 30322; Max-Planck Institut für Molekulare Genetik, Ihnestrasse 73, D-14195, Berlin, Germany; University of California,-Davis, Center for Neuroscience, 1544 Newton Court, Davis, California, 95616Division of Medical and Molecular Genetics, GKT School of Medicine, King's College, London, United Kingdom; Department of Neurology, Faculty of Medicine, Academic Hospital Nijmegen, The Netherlands; Laboratory of Molecular Neuropharmacology, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, 15261; Department of Genetics, Emory University, Atlanta, Georgia, 30322; Max-Planck Institut für Molekulare Genetik, Ihnestrasse 73, D-14195, Berlin, Germany; University of California,-Davis, Center for Neuroscience, 1544 Newton Court, Davis, California, 95616Huntington's disease (HD) is a late onset neurodegenerative disorder caused by a CAG/polyglutamine (polyQ) repeat expansion. PolyQ aggregates can be detected in the nuclei and processes of neurons in HD patients and mouse models prior to the onset of symptoms. The misfolding and aggregation pathway is an important therapeutic target. To better test the efficacy of aggregation inhibitors, we have developed an organotypic slice culture system. We show here that the formation of polyQ aggregates in hippocampal slices established from the R6/2 mouse follows the same prescribed sequence as occurs in vivo. Using this assay, we show that Congo red and chrysamine G can modulate aggregate formation, but show complex dose–response curves. Oral administration of creatine has been shown to delay the onset of all aspects of the phenotype and neuropathology in R6/2 mice. We show here that creatine can similarly inhibit aggregate formation in the slice culture assay.http://www.sciencedirect.com/science/article/pii/S0969996101904383 |