Molecular and structural architecture of polyQ aggregates in yeast

• Verfasst von: Gruber, Anselm [VerfasserIn]
• Verfasst von: Lüchtenborg, Christian [VerfasserIn]
• Verfasst von: Sachsenheimer, Timo [VerfasserIn]
• Verfasst von: Brügger, Britta [VerfasserIn]
• Titel: Molecular and structural architecture of polyQ aggregates in yeast
• Verf.angabe: Anselm Gruber, Daniel Hornburg, Matthias Antonin, Natalie Krahmer, Javier Collado, Miroslava Schaffer, Greta Zubaite, Christian Lüchtenborg, Timo Sachsenheimer, Britta Brügger, Matthias Mann, Wolfgang Baumeister, F. Ulrich Hartl, Mark S. Hipp, and Rubén Fernández-Busnadiego
• E-Jahr: 2018
• Jahr: March 26, 2018
• Umfang: 8 S.
• Fussnoten: Gesehen am 20.05.2019
• Titel Quelle: Enthalten in: National Academy of Sciences (Washington, DC)Proceedings of the National Academy of Sciences of the United States of America
• Ort Quelle: Washington, DC : National Acad. of Sciences, 1915
• Jahr Quelle: 2018
• Band/Heft Quelle: 115(2018), 15, Seite E3446-E3453
• ISSN Quelle: 1091-6490
• DOI: doi:10.1073/pnas.1717978115
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: cryo-electron microscopy
• Sach-SW: cryo-focused ion beam milling
• Sach-SW: label-free mass spectrometry
• Sach-SW: neurodegeneration
• Sach-SW: protein aggregation
• K10plus-PPN: 1665940662

Abstract

Huntington’s disease is caused by the expansion of a polyglutamine (polyQ) tract in the N-terminal exon of huntingtin (HttEx1), but the cellular mechanisms leading to neurodegeneration remain poorly understood. Here we present in situ structural studies by cryo-electron tomography of an established yeast model system of polyQ toxicity. We find that expression of polyQ-expanded HttEx1 results in the formation of unstructured inclusion bodies and in some cases fibrillar aggregates. This contrasts with recent findings in mammalian cells, where polyQ inclusions were exclusively fibrillar. In yeast, polyQ toxicity correlates with alterations in mitochondrial and lipid droplet morphology, which do not arise from physical interactions with inclusions or fibrils. Quantitative proteomic analysis shows that polyQ aggregates sequester numerous cellular proteins and cause a major change in proteome composition, most significantly in proteins related to energy metabolism. Thus, our data point to a multifaceted toxic gain-of-function of polyQ aggregates, driven by sequestration of endogenous proteins and mitochondrial and lipid droplet dysfunction.