Molecular and structural architecture of polyQ aggregates in yeast

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; Rubén Fernández-Busnadiego

doi:10.1073/pnas.1717978115

Molecular and structural architecture of polyQ aggregates in yeast

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, Rubén Fernández-Busnadiego

20 Citations (Scopus)

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.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1717978115
Publication status	Published - 2018
Externally published	Yes

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Gruber, A., Hornburg, D., Antonin, M., Krahmer, N., Collado, J., Schaffer, M., Zubaite, G., Lüchtenborg, C., Sachsenheimer, T., Brügger, B., Mann, M., Baumeister, W., Hartl, F. U., Hipp, M. S., & Fernández-Busnadiego, R. (2018). Molecular and structural architecture of polyQ aggregates in yeast. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1717978115

Gruber, A, Hornburg, D, Antonin, M, Krahmer, N, Collado, J, Schaffer, M, Zubaite, G, Lüchtenborg, C, Sachsenheimer, T, Brügger, B, Mann, M, Baumeister, W, Hartl, FU, Hipp, MS & Fernández-Busnadiego, R 2018, 'Molecular and structural architecture of polyQ aggregates in yeast', Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.1717978115

@article{e825ce03495344d1b1beda585019ff33,

title = "Molecular and structural architecture of polyQ aggregates in yeast",

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.",

author = "Anselm Gruber and Daniel Hornburg and Matthias Antonin and Natalie Krahmer and Javier Collado and Miroslava Schaffer and Greta Zubaite and Christian L{\"u}chtenborg and Timo Sachsenheimer and Britta Br{\"u}gger and Matthias Mann and Wolfgang Baumeister and Hartl, {F Ulrich} and Hipp, {Mark S} and Rub{\'e}n Fern{\'a}ndez-Busnadiego",

year = "2018",

doi = "10.1073/pnas.1717978115",

language = "English",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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TY - JOUR

T1 - Molecular and structural architecture of polyQ aggregates in yeast

AU - Gruber, Anselm

AU - Hornburg, Daniel

AU - Antonin, Matthias

AU - Krahmer, Natalie

AU - Collado, Javier

AU - Schaffer, Miroslava

AU - Zubaite, Greta

AU - Lüchtenborg, Christian

AU - Sachsenheimer, Timo

AU - Brügger, Britta

AU - Mann, Matthias

AU - Baumeister, Wolfgang

AU - Hartl, F Ulrich

AU - Hipp, Mark S

AU - Fernández-Busnadiego, Rubén

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1717978115

DO - 10.1073/pnas.1717978115

M3 - Journal article

C2 - 29581260

SN - 0027-8424

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

ER -

Molecular and structural architecture of polyQ aggregates in yeast

Abstract

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