Molecular and structural architecture of polyQ aggregates in yeast

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 15; pp. E3446 - E3453
• Main Authors: Gruber, Anselm, Hornburg, Daniel, Antonin, Matthias, Krahmer, Natalie, Collado, Javier, Schaffer, Miroslava, Zubaite, Greta, Lüchtenborg, Christian, Sachsenheimer, Timo, Brügger, Britta, Mann, Matthias, Baumeister, Wolfgang, Hartl, F. Ulrich, Hipp, Mark S., Fernández-Busnadiego, Rubén
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10-04-2018
• Series: PNAS Plus
• Subjects: Aggregates; Biological Sciences; Data points; Energy metabolism; Fibrils; Humans; Huntingtin; Huntington Disease - genetics; Huntington Disease - metabolism; Huntingtons disease; Inclusion bodies; Inclusion Bodies - chemistry; Inclusion Bodies - genetics; Inclusion Bodies - metabolism; Inclusions; Lipid Droplets - chemistry; Lipid Droplets - metabolism; Mammalian cells; Mass spectrometry; Metabolism; Mitochondria; Mitochondria - chemistry; Mitochondria - metabolism; Morphology; Neurodegeneration; Peptides - chemistry; Peptides - metabolism; Peptides - toxicity; PNAS Plus; Polyglutamine; Proteins; Proteomes; Proteomics; Saccharomyces cerevisiae - chemistry; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Toxicity; Trinucleotide repeat diseases; Yeast; neurodegeneration; cryo-focused ion beam milling; label-free mass spectrometry; protein aggregation; cryo-electron microscopy
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1717978115

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 cryoelectron 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.