Molecular and structural architecture of polyQ aggregates in yeast

Research output: Contribution to journal › Journal article › Research › peer-review

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Molecular and structural architecture of polyQ aggregates in yeast. / 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.

In: Proceedings of the National Academy of Sciences of the United States of America, 2018.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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

APA

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

Vancouver

Gruber A, Hornburg D, Antonin M, Krahmer N, Collado J, Schaffer M et al. Molecular and structural architecture of polyQ aggregates in yeast. Proceedings of the National Academy of Sciences of the United States of America. 2018. https://doi.org/10.1073/pnas.1717978115

Author

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. / Molecular and structural architecture of polyQ aggregates in yeast. In: Proceedings of the National Academy of Sciences of the United States of America. 2018.

Bibtex

@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",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",

}

RIS

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

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

SN - 0027-8424

ER -

ID: 194518165