title: Polyglutamine repeat length-dependent proteolysis of huntingtin.
abstract: Amino-terminal fragments of huntingtin, which contain the expanded polyglutamine repeat, have been proposed to contribute to the pathology of Huntington's disease (HD). Data supporting this claim have been generated from patients with HD in which truncated amino-terminal fragments forming intranuclear inclusions have been observed, and from animal and cell-based models of HD where it has been demonstrated that truncated polyglutamine-containing fragments of htt are more toxic than full-length huntingtin. We report here the identification of a region within huntingtin, spanning from amino acids 63 to 111, that is cleaved in cultured cells to generate a fragment of similar size to those observed in patients with HD. Importantly, proteolytic cleavage within this region appears dependent upon the length of the polyglutamine repeat within huntingtin, with pathological polyglutamine repeat-containing huntingtin being more efficiently cleaved than huntingtin containing polyglutamine repeats of nonpathological size.
authors.affiliation: Amgen Inc., Thousand Oaks, California 91320, USA.
authors.forename: Banghua
authors.initials: B
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Fan
authors.forename: Aldona
authors.initials: A
authors.lastname: Balciunas
authors.forename: Jillian K
authors.initials: JK
authors.lastname: Cooper
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
authors.forename: Shirley
authors.initials: S
authors.lastname: Steavenson
authors.forename: Paul E
authors.initials: PE
authors.lastname: Denis
authors.forename: Yunjen
authors.initials: Y
authors.lastname: Young
authors.forename: Beverly
authors.initials: B
authors.lastname: Adler
authors.forename: Larry
authors.initials: L
authors.lastname: Daugherty
authors.forename: Raffi
authors.initials: R
authors.lastname: Manoukian
authors.forename: Gary
authors.initials: G
authors.lastname: Elliott
authors.forename: Wenyan
authors.initials: W
authors.lastname: Shen
authors.forename: Jane
authors.initials: J
authors.lastname: Talvenheimo
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Haniu
authors.forename: Raj
authors.initials: R
authors.lastname: Haldankar
authors.forename: Jette
authors.initials: J
authors.lastname: Wypych
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Martin
authors.initials: M
authors.lastname: Citron
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002154:Calpain / Q000378:metabolism; D002460:Cell Line; D003342:Corpus Striatum / Q000166:cytology; D018604:Epitope Mapping; D017353:Gene Deletion; D000071058:Huntingtin Protein; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; C097188:polyglutamine; D002154:Calpain