Spatiotemporal Proteomic Profiling of Huntington’s Disease Inclusions Reveals Widespread Loss of Protein Function
Aggregation of polyglutamine-expanded huntingtin exon 1 (HttEx1) in Huntington’s disease (HD) proceeds from soluble oligomers to late-stage inclusions. The nature of the aggregates and how they lead to neuronal dysfunction is not well understood. We employed mass spectrometry (MS)-based quantitative...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-11-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717315772 |
| id |
doaj-6eb49d931f08402aa04d09c42c8ca559 |
|---|---|
| record_format |
Article |
| spelling |
doaj-6eb49d931f08402aa04d09c42c8ca5592020-11-25T00:12:11ZengElsevierCell Reports2211-12472017-11-012182291230310.1016/j.celrep.2017.10.097Spatiotemporal Proteomic Profiling of Huntington’s Disease Inclusions Reveals Widespread Loss of Protein FunctionFabian Hosp0Sara Gutiérrez-Ángel1Martin H. Schaefer2Jürgen Cox3Felix Meissner4Mark S. Hipp5F.-Ulrich Hartl6Rüdiger Klein7Irina Dudanova8Matthias Mann9Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, GermanyDepartment Molecules-Signaling-Development, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, GermanyEMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, SpainComputational Systems Biochemistry Laboratory, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, GermanyExperimental Systems Immunology Laboratory, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, GermanyDepartment of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, GermanyDepartment of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, GermanyDepartment Molecules-Signaling-Development, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, GermanyDepartment Molecules-Signaling-Development, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, GermanyDepartment of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, GermanyAggregation of polyglutamine-expanded huntingtin exon 1 (HttEx1) in Huntington’s disease (HD) proceeds from soluble oligomers to late-stage inclusions. The nature of the aggregates and how they lead to neuronal dysfunction is not well understood. We employed mass spectrometry (MS)-based quantitative proteomics to dissect spatiotemporal mechanisms of neurodegeneration using the R6/2 mouse model of HD. Extensive remodeling of the soluble brain proteome correlated with insoluble aggregate formation during disease progression. In-depth and quantitative characterization of the aggregates uncovered an unprecedented complexity of several hundred proteins. Sequestration to aggregates depended on protein expression levels and sequence features such as low-complexity regions or coiled-coil domains. In a cell-based HD model, overexpression of a subset of the sequestered proteins in most cases rescued viability and reduced aggregate size. Our spatiotemporally resolved proteome resource of HD progression indicates that widespread loss of cellular protein function contributes to aggregate-mediated toxicity.http://www.sciencedirect.com/science/article/pii/S2211124717315772Huntington’s diseaseinclusion bodiescerebrospinal fluidneurodegenerationquantitative proteomics |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Fabian Hosp Sara Gutiérrez-Ángel Martin H. Schaefer Jürgen Cox Felix Meissner Mark S. Hipp F.-Ulrich Hartl Rüdiger Klein Irina Dudanova Matthias Mann |
| spellingShingle |
Fabian Hosp Sara Gutiérrez-Ángel Martin H. Schaefer Jürgen Cox Felix Meissner Mark S. Hipp F.-Ulrich Hartl Rüdiger Klein Irina Dudanova Matthias Mann Spatiotemporal Proteomic Profiling of Huntington’s Disease Inclusions Reveals Widespread Loss of Protein Function Cell Reports Huntington’s disease inclusion bodies cerebrospinal fluid neurodegeneration quantitative proteomics |
| author_facet |
Fabian Hosp Sara Gutiérrez-Ángel Martin H. Schaefer Jürgen Cox Felix Meissner Mark S. Hipp F.-Ulrich Hartl Rüdiger Klein Irina Dudanova Matthias Mann |
| author_sort |
Fabian Hosp |
| title |
Spatiotemporal Proteomic Profiling of Huntington’s Disease Inclusions Reveals Widespread Loss of Protein Function |
| title_short |
Spatiotemporal Proteomic Profiling of Huntington’s Disease Inclusions Reveals Widespread Loss of Protein Function |
| title_full |
Spatiotemporal Proteomic Profiling of Huntington’s Disease Inclusions Reveals Widespread Loss of Protein Function |
| title_fullStr |
Spatiotemporal Proteomic Profiling of Huntington’s Disease Inclusions Reveals Widespread Loss of Protein Function |
| title_full_unstemmed |
Spatiotemporal Proteomic Profiling of Huntington’s Disease Inclusions Reveals Widespread Loss of Protein Function |
| title_sort |
spatiotemporal proteomic profiling of huntington’s disease inclusions reveals widespread loss of protein function |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2017-11-01 |
| description |
Aggregation of polyglutamine-expanded huntingtin exon 1 (HttEx1) in Huntington’s disease (HD) proceeds from soluble oligomers to late-stage inclusions. The nature of the aggregates and how they lead to neuronal dysfunction is not well understood. We employed mass spectrometry (MS)-based quantitative proteomics to dissect spatiotemporal mechanisms of neurodegeneration using the R6/2 mouse model of HD. Extensive remodeling of the soluble brain proteome correlated with insoluble aggregate formation during disease progression. In-depth and quantitative characterization of the aggregates uncovered an unprecedented complexity of several hundred proteins. Sequestration to aggregates depended on protein expression levels and sequence features such as low-complexity regions or coiled-coil domains. In a cell-based HD model, overexpression of a subset of the sequestered proteins in most cases rescued viability and reduced aggregate size. Our spatiotemporally resolved proteome resource of HD progression indicates that widespread loss of cellular protein function contributes to aggregate-mediated toxicity. |
| topic |
Huntington’s disease inclusion bodies cerebrospinal fluid neurodegeneration quantitative proteomics |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124717315772 |
| work_keys_str_mv |
AT fabianhosp spatiotemporalproteomicprofilingofhuntingtonsdiseaseinclusionsrevealswidespreadlossofproteinfunction AT saragutierrezangel spatiotemporalproteomicprofilingofhuntingtonsdiseaseinclusionsrevealswidespreadlossofproteinfunction AT martinhschaefer spatiotemporalproteomicprofilingofhuntingtonsdiseaseinclusionsrevealswidespreadlossofproteinfunction AT jurgencox spatiotemporalproteomicprofilingofhuntingtonsdiseaseinclusionsrevealswidespreadlossofproteinfunction AT felixmeissner spatiotemporalproteomicprofilingofhuntingtonsdiseaseinclusionsrevealswidespreadlossofproteinfunction AT markshipp spatiotemporalproteomicprofilingofhuntingtonsdiseaseinclusionsrevealswidespreadlossofproteinfunction AT fulrichhartl spatiotemporalproteomicprofilingofhuntingtonsdiseaseinclusionsrevealswidespreadlossofproteinfunction AT rudigerklein spatiotemporalproteomicprofilingofhuntingtonsdiseaseinclusionsrevealswidespreadlossofproteinfunction AT irinadudanova spatiotemporalproteomicprofilingofhuntingtonsdiseaseinclusionsrevealswidespreadlossofproteinfunction AT matthiasmann spatiotemporalproteomicprofilingofhuntingtonsdiseaseinclusionsrevealswidespreadlossofproteinfunction |
| _version_ |
1725400658742345728 |