Soluble Oligomers of PolyQ-Expanded Huntingtin Target a Multiplicity of Key Cellular Factors

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

Standard

Soluble Oligomers of PolyQ-Expanded Huntingtin Target a Multiplicity of Key Cellular Factors. / Kim, Yujin E; Hosp, Fabian; Frottin, Frédéric; Ge, Hui; Mann, Matthias; Hayer-Hartl, Manajit; Hartl, F Ulrich.

In: Molecular Cell, Vol. 63, No. 6, 15.09.2016, p. 951-64.

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

Harvard

Kim, YE, Hosp, F, Frottin, F, Ge, H, Mann, M, Hayer-Hartl, M & Hartl, FU 2016, 'Soluble Oligomers of PolyQ-Expanded Huntingtin Target a Multiplicity of Key Cellular Factors', Molecular Cell, vol. 63, no. 6, pp. 951-64. https://doi.org/10.1016/j.molcel.2016.07.022

APA

Kim, Y. E., Hosp, F., Frottin, F., Ge, H., Mann, M., Hayer-Hartl, M., & Hartl, F. U. (2016). Soluble Oligomers of PolyQ-Expanded Huntingtin Target a Multiplicity of Key Cellular Factors. Molecular Cell, 63(6), 951-64. https://doi.org/10.1016/j.molcel.2016.07.022

Vancouver

Kim YE, Hosp F, Frottin F, Ge H, Mann M, Hayer-Hartl M et al. Soluble Oligomers of PolyQ-Expanded Huntingtin Target a Multiplicity of Key Cellular Factors. Molecular Cell. 2016 Sep 15;63(6):951-64. https://doi.org/10.1016/j.molcel.2016.07.022

Author

Kim, Yujin E ; Hosp, Fabian ; Frottin, Frédéric ; Ge, Hui ; Mann, Matthias ; Hayer-Hartl, Manajit ; Hartl, F Ulrich. / Soluble Oligomers of PolyQ-Expanded Huntingtin Target a Multiplicity of Key Cellular Factors. In: Molecular Cell. 2016 ; Vol. 63, No. 6. pp. 951-64.

Bibtex

@article{f44b4645a97141e8898db11801bcab14,
title = "Soluble Oligomers of PolyQ-Expanded Huntingtin Target a Multiplicity of Key Cellular Factors",
abstract = "Huntington's disease is one of several neurodegenerative disorders characterized by the aggregation of polyglutamine (polyQ)-expanded mutant protein. How polyQ aggregation leads to cellular dysfunction is not well understood. Here, we analyzed aberrant protein interactions of soluble oligomers and insoluble inclusions of mutant huntingtin using in-cell single molecule fluorescence spectroscopy and quantitative proteomics. We find that the interactome of soluble oligomers is highly complex, with an enrichment of RNA-binding proteins as well as proteins functioning in ribosome biogenesis, translation, transcription, and vesicle transport. The oligomers frequently target proteins containing extended low-complexity sequences, potentially interfering with key cellular pathways. In contrast, the insoluble inclusions are less interactive and associate strongly with protein quality control components, such as Hsp40 chaperones and factors of the ubiquitin-proteasome system. Our results suggest a {"}multiple hit{"} model for the pathogenic effects of mutant huntingtin, with soluble forms engaging more extensively in detrimental interactions than insoluble aggregates.",
keywords = "Animals, Bacterial Proteins, Cell Line, Tumor, Gene Expression, Gene Ontology, Green Fluorescent Proteins, HSP40 Heat-Shock Proteins, HeLa Cells, Humans, Huntingtin Protein, Luminescent Proteins, Mice, Molecular Sequence Annotation, Mutation, Neurons, Peptides, Protein Aggregates, Protein Interaction Mapping, Protein Multimerization, Recombinant Fusion Proteins, Ribosomal Proteins, Single Molecule Imaging, Solubility, Spectrometry, Fluorescence, Journal Article",
author = "Kim, {Yujin E} and Fabian Hosp and Fr{\'e}d{\'e}ric Frottin and Hui Ge and Matthias Mann and Manajit Hayer-Hartl and Hartl, {F Ulrich}",
note = "Copyright {\textcopyright} 2016 Elsevier Inc. All rights reserved.",
year = "2016",
month = sep,
day = "15",
doi = "10.1016/j.molcel.2016.07.022",
language = "English",
volume = "63",
pages = "951--64",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",

}

RIS

TY - JOUR

T1 - Soluble Oligomers of PolyQ-Expanded Huntingtin Target a Multiplicity of Key Cellular Factors

AU - Kim, Yujin E

AU - Hosp, Fabian

AU - Frottin, Frédéric

AU - Ge, Hui

AU - Mann, Matthias

AU - Hayer-Hartl, Manajit

AU - Hartl, F Ulrich

N1 - Copyright © 2016 Elsevier Inc. All rights reserved.

PY - 2016/9/15

Y1 - 2016/9/15

N2 - Huntington's disease is one of several neurodegenerative disorders characterized by the aggregation of polyglutamine (polyQ)-expanded mutant protein. How polyQ aggregation leads to cellular dysfunction is not well understood. Here, we analyzed aberrant protein interactions of soluble oligomers and insoluble inclusions of mutant huntingtin using in-cell single molecule fluorescence spectroscopy and quantitative proteomics. We find that the interactome of soluble oligomers is highly complex, with an enrichment of RNA-binding proteins as well as proteins functioning in ribosome biogenesis, translation, transcription, and vesicle transport. The oligomers frequently target proteins containing extended low-complexity sequences, potentially interfering with key cellular pathways. In contrast, the insoluble inclusions are less interactive and associate strongly with protein quality control components, such as Hsp40 chaperones and factors of the ubiquitin-proteasome system. Our results suggest a "multiple hit" model for the pathogenic effects of mutant huntingtin, with soluble forms engaging more extensively in detrimental interactions than insoluble aggregates.

AB - Huntington's disease is one of several neurodegenerative disorders characterized by the aggregation of polyglutamine (polyQ)-expanded mutant protein. How polyQ aggregation leads to cellular dysfunction is not well understood. Here, we analyzed aberrant protein interactions of soluble oligomers and insoluble inclusions of mutant huntingtin using in-cell single molecule fluorescence spectroscopy and quantitative proteomics. We find that the interactome of soluble oligomers is highly complex, with an enrichment of RNA-binding proteins as well as proteins functioning in ribosome biogenesis, translation, transcription, and vesicle transport. The oligomers frequently target proteins containing extended low-complexity sequences, potentially interfering with key cellular pathways. In contrast, the insoluble inclusions are less interactive and associate strongly with protein quality control components, such as Hsp40 chaperones and factors of the ubiquitin-proteasome system. Our results suggest a "multiple hit" model for the pathogenic effects of mutant huntingtin, with soluble forms engaging more extensively in detrimental interactions than insoluble aggregates.

KW - Animals

KW - Bacterial Proteins

KW - Cell Line, Tumor

KW - Gene Expression

KW - Gene Ontology

KW - Green Fluorescent Proteins

KW - HSP40 Heat-Shock Proteins

KW - HeLa Cells

KW - Humans

KW - Huntingtin Protein

KW - Luminescent Proteins

KW - Mice

KW - Molecular Sequence Annotation

KW - Mutation

KW - Neurons

KW - Peptides

KW - Protein Aggregates

KW - Protein Interaction Mapping

KW - Protein Multimerization

KW - Recombinant Fusion Proteins

KW - Ribosomal Proteins

KW - Single Molecule Imaging

KW - Solubility

KW - Spectrometry, Fluorescence

KW - Journal Article

U2 - 10.1016/j.molcel.2016.07.022

DO - 10.1016/j.molcel.2016.07.022

M3 - Journal article

C2 - 27570076

VL - 63

SP - 951

EP - 964

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 6

ER -

ID: 184324471