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Spatiotemporal Proteomic Profiling of Huntington's Disease Inclusions Reveals Widespread Loss of Protein Function.

Authors
  • Hosp, Fabian1
  • Gutiérrez-Ángel, Sara2
  • Schaefer, Martin H3
  • Cox, Jürgen4
  • Meissner, Felix5
  • Hipp, Mark S6
  • Hartl, F-Ulrich6
  • Klein, Rüdiger7
  • Dudanova, Irina8
  • Mann, Matthias9
  • 1 Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. , (Germany)
  • 2 Department Molecules-Signaling-Development, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany. , (Germany)
  • 3 EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain. , (Spain)
  • 4 Computational Systems Biochemistry Laboratory, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. , (Germany)
  • 5 Experimental Systems Immunology Laboratory, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. , (Germany)
  • 6 Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany. , (Germany)
  • 7 Department Molecules-Signaling-Development, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany. , (Germany)
  • 8 Department Molecules-Signaling-Development, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany. Electronic address: [email protected] , (Germany)
  • 9 Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany. Electronic address: [email protected] , (Germany)
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Nov 21, 2017
Volume
21
Issue
8
Pages
2291–2303
Identifiers
DOI: 10.1016/j.celrep.2017.10.097
PMID: 29166617
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

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