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.
authors: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82159 Martinsried, Germany.
authors: Yujin E
authors: YE
authors: Kim
authors: Department of Proteomics & Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82159 Martinsried, Germany.
authors: Fabian
authors: F
authors: Hosp
authors: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82159 Martinsried, Germany.
authors: Frédéric
authors: F
authors: Frottin
authors: Novartis Institutes for Biomedical Research, No. 2 BoYun Road, Pudong, Shanghai 201203, China.
authors: Hui
authors: H
authors: Ge
authors: Department of Proteomics & Signal Transduction, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82159 Martinsried, Germany.
authors: Matthias
authors: M
authors: Mann
authors: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82159 Martinsried, Germany. Electronic address: mhartl@biochem.mpg.de.
authors: Manajit
authors: M
authors: Hayer-Hartl
authors: Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82159 Martinsried, Germany; Munich Cluster for Systems Neurology, Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Schillerstrasse 44, 80336 München, Germany. Electronic address: uhartl@biochem.mpg.de.
authors: F Ulrich
authors: FU
authors: Hartl
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015870:Gene Expression; D063990:Gene Ontology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D058977:Molecular Sequence Annotation; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D000072760:Single Molecule Imaging / Q000379:methods*; D012995:Solubility; D013050:Spectrometry, Fluorescence; D000097573:Red Fluorescent Protein
chemical_list: D001426:Bacterial Proteins; D049452:Green Fluorescent Proteins; D050956:HSP40 Heat-Shock Proteins; D000071058:Huntingtin Protein; D008164:Luminescent Proteins; D010455:Peptides; D066329:Protein Aggregates; D011993:Recombinant Fusion Proteins; D012269:Ribosomal Proteins; D000097573:Red Fluorescent Protein; C086055:HTT protein, human; C506812:Htt protein, mouse; C000620222:RPS2 protein, human; C054562:yellow fluorescent protein, Bacteria; C097188:polyglutamine