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

TY - JOUR

T1 - Spatiotemporal Proteomic Profiling of Huntington's Disease Inclusions Reveals Widespread Loss of Protein Function

AU - Hosp, Fabian

AU - Gutiérrez-Ángel, Sara

AU - Schaefer, Martin H

AU - Cox, Jürgen

AU - Meissner, Felix

AU - Hipp, Mark S

AU - Hartl, F-Ulrich

AU - Klein, Rüdiger

AU - Dudanova, Irina

AU - Mann, Matthias

N1 - Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2017/11/21

Y1 - 2017/11/21

N2 - 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. 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.

AB - 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. 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.

KW - Journal Article

U2 - 10.1016/j.celrep.2017.10.097

DO - 10.1016/j.celrep.2017.10.097

M3 - Journal article

C2 - 29166617

SN - 2639-1856

VL - 21

SP - 2291

EP - 2303

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -