Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract
Many neurodegenerative diseases are linked to amyloid aggregation. In Huntington’s disease (HD), neurotoxicity correlates with an increased aggregation propensity of a polyglutamine (polyQ) expansion in exon 1 of mutant huntingtin protein (mHtt). Here we establish how the domains flanking the polyQ...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2016-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/18065 |
| _version_ | 1811200093388275712 |
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| author | Koning Shen Barbara Calamini Jonathan A Fauerbach Boxue Ma Sarah H Shahmoradian Ivana L Serrano Lachapel Wah Chiu Donald C Lo Judith Frydman |
| author_facet | Koning Shen Barbara Calamini Jonathan A Fauerbach Boxue Ma Sarah H Shahmoradian Ivana L Serrano Lachapel Wah Chiu Donald C Lo Judith Frydman |
| author_sort | Koning Shen |
| collection | DOAJ |
| description | Many neurodegenerative diseases are linked to amyloid aggregation. In Huntington’s disease (HD), neurotoxicity correlates with an increased aggregation propensity of a polyglutamine (polyQ) expansion in exon 1 of mutant huntingtin protein (mHtt). Here we establish how the domains flanking the polyQ tract shape the mHtt conformational landscape in vitro and in neurons. In vitro, the flanking domains have opposing effects on the conformation and stabilities of oligomers and amyloid fibrils. The N-terminal N17 promotes amyloid fibril formation, while the C-terminal Proline Rich Domain destabilizes fibrils and enhances oligomer formation. However, in neurons both domains act synergistically to engage protective chaperone and degradation pathways promoting mHtt proteostasis. Surprisingly, when proteotoxicity was assessed in rat corticostriatal brain slices, either flanking region alone sufficed to generate a neurotoxic conformation, while the polyQ tract alone exhibited minimal toxicity. Linking mHtt structural properties to its neuronal proteostasis should inform new strategies for neuroprotection in polyQ-expansion diseases. |
| first_indexed | 2024-04-12T01:58:59Z |
| format | Article |
| id | doaj.art-3db1d5e751fe4e55945a6a20452f119f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:58:59Z |
| publishDate | 2016-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3db1d5e751fe4e55945a6a20452f119f2022-12-22T03:52:43ZengeLife Sciences Publications LtdeLife2050-084X2016-10-01510.7554/eLife.18065Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tractKoning Shen0https://orcid.org/0000-0003-2607-449XBarbara Calamini1Jonathan A Fauerbach2Boxue Ma3Sarah H Shahmoradian4Ivana L Serrano Lachapel5Wah Chiu6Donald C Lo7Judith Frydman8https://orcid.org/0000-0003-2302-6943Department of Biology, Stanford University, Stanford, United States; Department of Genetics, Stanford University, Stanford, United StatesCenter for Drug Discovery, Department of Neurobiology, Duke University Medical Center, Durham, United StatesDepartment of Biology, Stanford University, Stanford, United States; Department of Genetics, Stanford University, Stanford, United StatesVerna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United StatesVerna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United StatesDepartment of Biology, Stanford University, Stanford, United States; Department of Genetics, Stanford University, Stanford, United StatesVerna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United StatesCenter for Drug Discovery, Department of Neurobiology, Duke University Medical Center, Durham, United StatesDepartment of Biology, Stanford University, Stanford, United States; Department of Genetics, Stanford University, Stanford, United StatesMany neurodegenerative diseases are linked to amyloid aggregation. In Huntington’s disease (HD), neurotoxicity correlates with an increased aggregation propensity of a polyglutamine (polyQ) expansion in exon 1 of mutant huntingtin protein (mHtt). Here we establish how the domains flanking the polyQ tract shape the mHtt conformational landscape in vitro and in neurons. In vitro, the flanking domains have opposing effects on the conformation and stabilities of oligomers and amyloid fibrils. The N-terminal N17 promotes amyloid fibril formation, while the C-terminal Proline Rich Domain destabilizes fibrils and enhances oligomer formation. However, in neurons both domains act synergistically to engage protective chaperone and degradation pathways promoting mHtt proteostasis. Surprisingly, when proteotoxicity was assessed in rat corticostriatal brain slices, either flanking region alone sufficed to generate a neurotoxic conformation, while the polyQ tract alone exhibited minimal toxicity. Linking mHtt structural properties to its neuronal proteostasis should inform new strategies for neuroprotection in polyQ-expansion diseases.https://elifesciences.org/articles/18065Huntington's diseaseproteostasisaggregation |
| spellingShingle | Koning Shen Barbara Calamini Jonathan A Fauerbach Boxue Ma Sarah H Shahmoradian Ivana L Serrano Lachapel Wah Chiu Donald C Lo Judith Frydman Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract eLife Huntington's disease proteostasis aggregation |
| title | Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract |
| title_full | Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract |
| title_fullStr | Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract |
| title_full_unstemmed | Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract |
| title_short | Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract |
| title_sort | control of the structural landscape and neuronal proteotoxicity of mutant huntingtin by domains flanking the polyq tract |
| topic | Huntington's disease proteostasis aggregation |
| url | https://elifesciences.org/articles/18065 |
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