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

• Published in: Cell reports (Cambridge) Vol. 21; no. 8; pp. 2291 - 2303
• Main Authors: Hosp, Fabian, Gutiérrez-Ángel, Sara, Schaefer, Martin H., Cox, Jürgen, Meissner, Felix, Hipp, Mark S., Hartl, F.-Ulrich, Klein, Rüdiger, Dudanova, Irina, Mann, Matthias
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-11-2017; Elsevier; Cell Press
• Subjects: Animals; Cerebrospinal fluid; Disease Models, Animal; Gene Expression Profiling - methods; Huntington Disease - genetics; Huntington's disease; Inclusion bodies; Inclusion Bodies - metabolism; Mice, Transgenic; Nerve Tissue Proteins - metabolism; Neurodegeneration; Neurons - metabolism; Nuclear Proteins - metabolism; Peptides - genetics; Proteomics - methods; Quantitative proteomics; neurodegeneration; Huntington’s disease; inclusion bodies; quantitative proteomics; cerebrospinal fluid
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.10.097

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.
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•Spatiotemporally resolved brain proteome of wild-type and HD mice•Quantitative characterization of huntingtin inclusion bodies in vivo•Sequestration correlates with protein expression levels and specific sequence features•Resupplying sequestered proteins ameliorates HTT-induced toxicity and inclusion size
Hosp et al. use quantitative proteomics to describe the soluble and insoluble proteome of several brain regions in a mouse model of Huntington’s disease at various stages of disease progression. Their findings suggest that widespread sequestration of proteins into mutant huntingtin inclusion bodies contributes to HD pathogenesis.