title: Dynamic recruitment of active proteasomes into polyglutamine initiated inclusion bodies.
abstract: Neurodegenerative disorders such as Huntington's disease are hallmarked by neuronal intracellular inclusion body formation. Whether proteasomes are irreversibly recruited into inclusion bodies in these protein misfolding disorders is a controversial subject. In addition, it has been proposed that the proteasomes may become clogged by the aggregated protein fragments, leading to impairment of the ubiquitin-proteasome system. Here, we show by fluorescence pulse-chase experiments in living cells that proteasomes are dynamically and reversibly recruited into inclusion bodies. As these recruited proteasomes remain catalytically active and accessible to substrates, our results challenge the concept of proteasome sequestration and impairment in Huntington's disease, and support the reported absence of proteasome impairment in mouse models of Huntington's disease.
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schipper-Krom
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, The Netherlands.
authors.forename: Katrin
authors.initials: K
authors.lastname: Juenemann
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, The Netherlands.
authors.forename: Anne H
authors.initials: AH
authors.lastname: Jansen
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, The Netherlands.
authors.forename: Anne
authors.initials: A
authors.lastname: Wiemhoefer
authors.affiliation: Department of Bio-Organic Synthesis, Institute of Chemistry, University of Leiden, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
authors.forename: Rianne
authors.initials: R
authors.lastname: van den Nieuwendijk
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, Great Maze Pond, SE1 9RT London, United Kingdom.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Smith
authors.affiliation: Section Molecular Cytology, Swammerdam Institute for Life Sciences, University of Amsterdam, Sciencepark 904, 1090 GE Amsterdam, The Netherlands.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hink
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, Great Maze Pond, SE1 9RT London, United Kingdom.
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.affiliation: Department of Bio-Organic Synthesis, Institute of Chemistry, University of Leiden, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
authors.forename: Hermen
authors.initials: H
authors.lastname: Overkleeft
authors.affiliation: Department of Cell Biology II, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Huib
authors.initials: H
authors.lastname: Ovaa
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, The Netherlands. Electronic address: e.a.reits@amc.uva.nl.
authors.forename: Eric
authors.initials: E
authors.lastname: Reits
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; D049452:Green Fluorescent Proteins; C097188:polyglutamine; C108898:PSMB4 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: ABP; Aggregate; C4; FRAP; HD; Huntington; IB; Polyglutamine; Proteasome; UPS; Ub; Ubiquitin; activity-based probe; fluorescence recovery after photobleaching; huntington’s disease; inclusion body; mHtt; mutant huntingtin; polyQ; polyglutamine; tetracysteine; ubiquitin; ubiquitin–proteasome system