Ubiquitin-conjugating enzyme E2-25K increases aggregate formation and cell death in polyglutamine diseases.
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.
de Pril
Remko
R
Graduate School Neurosciences Amsterdam, Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
Fischer
David F
DF
Roos
Raymund A C
RA
van Leeuwen
Fred W
FW
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*
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