Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo.
Recently, we identified a novel gene, MJD1, which contains an expanded CAG triplet repeat in Machado-Joseph disease. Here we report the induction of apoptosis in cultured cells expressing a portion of the MJD1 gene that includes the expanded CAG repeats. Cell death occurs only when the CAG repeat is translated into polyglutamine residues, which apparently precipitate in large covalently modified forms. We also created ataxic transgenic mice by expressing the expanded polyglutamine stretch in Purkinje cells. Our results demonstrate the potential involvement of the expanded polyglutamine as the common aetiological agent for inherited neurodegenerative diseases with CAG expansions.
Ikeda
H
H
Department of Pharmacology, Kyoto University Faculty of Medicine, Japan.
Yamaguchi
M
M
Sugai
S
S
Aze
Y
Y
Narumiya
S
S
Kakizuka
A
A
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics*; D000067699:Ataxin-3; D015153:Blotting, Western; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D011232:Chemical Precipitation; D018628:Gene Dosage; D000882:Haplorhini; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology; D017827:Machado-Joseph Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010452:Peptide Biosynthesis; D010455:Peptides / Q000235:genetics; D014176:Protein Biosynthesis; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D011689:Purkinje Cells / Q000473:pathology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins; D014157:Transcription Factors; D014162:Transfection; D018911:Trinucleotide Repeats
D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011506:Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse