Spatiotemporal Proteomic Profiling of Huntington’s Disease Inclusions Reveals Widespread Loss of Protein Function
Fabian Hosp,
Sara Gutiérrez-Ángel,
Martin H. Schaefer,
Jürgen Cox,
Felix Meissner,
Mark S. Hipp,
F.-Ulrich Hartl,
Rüdiger Klein,
Irina Dudanova,
Matthias Mann
Affiliations
Fabian Hosp
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
Sara Gutiérrez-Ángel
Department Molecules-Signaling-Development, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany
Martin H. Schaefer
EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain
Jürgen Cox
Computational Systems Biochemistry Laboratory, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
Felix Meissner
Experimental Systems Immunology Laboratory, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
Mark S. Hipp
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
F.-Ulrich Hartl
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
Rüdiger Klein
Department Molecules-Signaling-Development, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany
Irina Dudanova
Department Molecules-Signaling-Development, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany
Matthias Mann
Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany
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.
