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Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation

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Item Type:Article
Title:Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation
Creators Name:Waelter, S. and Boeddrich, A. and Lurz, R. and Scherzinger, E. and Lueder, G. and Lehrach, H. and Wanker, E.E.
Abstract:The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 glutamines), but not with a polyglutamine tract in the normal range (20 glutamines), form aggresome-like perinuclear inclusions in human 293 Tet-Off cells. These structures contain aggregated, ubiquitinated huntingtin exon 1 protein with a characteristic fibrillar morphology. Inclusion bodies with truncated huntingtin protein are formed at centrosomes and are surrounded by vimentin filaments. Inhibition of proteasome activity resulted in a twofold increase in the amount of ubiquitinated, SDS-resistant aggregates, indicating that inclusion bodies accumulate when the capacity of the ubiquitin-proteasome system to degrade aggregation-prone huntingtin protein is exhausted. Immunofluorescence and electron microscopy with immunogold labeling revealed that the 20S, 19S, and 11S subunits of the 26S proteasome, the molecular chaperones BiP/GRP78, Hsp70, and Hsp40, as well as the RNA-binding protein TIA-1, the potential chaperone 14-3-3, and alpha-synuclein colocalize with the perinuclear inclusions. In 293 Tet-Off cells, inclusion body formation also resulted in cell toxicity and dramatic ultrastructural changes such as indentations and disruption of the nuclear envelope. Concentration of mitochondria around the inclusions and cytoplasmic vacuolation were also observed. Together these findings support the hypothesis that the ATP-dependent ubiquitin-proteasome system is a potential target for therapeutic interventions in glutamine repeat disorders.
Keywords:14-3-3 Proteins, Acetylcysteine, Carrier Proteins, Cell Line, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Exons, Heat-Shock Proteins, Huntington Disease, Immunoblotting, Inclusion Bodies, Membrane Proteins, Fluorescence Microscopy, Biological Models, Molecular Chaperones, Multienzyme Complexes, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Peptide Fragments, Poly(A)-Binding Proteins, Proteasome Endopeptidase Complex, Proteins, RNA-Binding Proteins, Recombinant Fusion Proteins, Synucleins, Transgenes, Tyrosine 3-Monooxygenase, Vimentinalpha-Synuclein
Source:Molecular Biology of the Cell
Publisher:American Society for Cell Biology
Page Range:1393-1407
Date:May 2001
Additional Information:Copyright (c) 2001 by The American Society for Cell Biology
Official Publication:http://www.molbiolcell.org/cgi/content/abstract/12/5/1393
PubMed:View item in PubMed

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