title: Ubiquitin-conjugating enzyme E2-25K increases aggregate formation and cell death in polyglutamine diseases.
abstract: Polyglutamine diseases are characterized by neuronal intranuclear inclusions of expanded polyglutamine proteins, which are also ubiquitinated, indicating impairment of the ubiquitin-proteasome system. E2-25K (Hip2), an ubiquitin-conjugating enzyme, interacts directly with huntingtin and may mediate ubiquitination of the neuronal intranuclear inclusions in Huntington disease. E2-25K could thus modulate aggregation and toxicity of expanded huntingtin. Here we show that E2-25K is involved in aggregate formation of expanded polyglutamine proteins and polyglutamine-induced cell death. Both a truncated mutant, lacking the catalytic tail domain, as well as a full antisense sequence, reduce aggregate formation. Strikingly, both E2-25K mutants also reduced polyglutamine-induced cell death. In postmortem brain material of both Huntington disease and SCA3, E2-25K staining of polyglutamine aggregates was observed in a subset of neurons bearing intranuclear neuronal inclusions. These results demonstrate that targeting by ubiquitination plays an important role in the pathology of polyglutamine diseases.
authors.affiliation: Graduate School Neurosciences Amsterdam, Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
authors.forename: Remko
authors.initials: R
authors.lastname: de Pril
authors.forename: David F
authors.initials: DF
authors.lastname: Fischer
authors.forename: Raymund A C
authors.initials: RA
authors.lastname: Roos
authors.forename: Fred W
authors.initials: FW
authors.lastname: van Leeuwen
mesh_terms: D001921:Brain / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D020134:Catalytic Domain / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D045586:Intranuclear Inclusion Bodies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017827:Machado-Joseph Disease / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; C100879:UBE2K protein, human; D044763:Ubiquitin-Conjugating Enzymes