title: Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA.
abstract: Dentatorubral and pallidoluysian atrophy (DRPLA) is a member of a family of progressive neurodegenerative diseases caused by polyglutamine repeat expansion. Transgenic mice expressing full-length human atrophin-1 with 65 consecutive glutamines exhibit ataxia, tremors, abnormal movements, seizures, and premature death. These mice accumulate atrophin-1 immunoreactivity and inclusion bodies in the nuclei of multiple populations of neurons. Subcellular fractionation revealed 120 kDa nuclear fragments of mutant atrophin-1, whose abundance increased with age and phenotypic severity. Brains of DRPLA patients contained apparently identical 120 kDa nuclear fragments. By contrast, mice overexpressing atrophin-1 with 26 glutamines were phenotypically normal and did not accumulate the 120 kDa fragments. We conclude that the evolution of neuropathology in DRPLA involves proteolytic processing of mutant atrophin-1 and nuclear accumulation of truncated fragments.
authors.affiliation: Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: G
authors.initials: G
authors.lastname: Schilling
authors.forename: J D
authors.initials: JD
authors.lastname: Wood
authors.forename: K
authors.initials: K
authors.lastname: Duan
authors.forename: H H
authors.initials: HH
authors.lastname: Slunt
authors.forename: V
authors.initials: V
authors.lastname: Gonzales
authors.forename: M
authors.initials: M
authors.lastname: Yamada
authors.forename: J K
authors.initials: JK
authors.lastname: Cooper
authors.forename: R L
authors.initials: RL
authors.lastname: Margolis
authors.forename: N A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: N G
authors.initials: NG
authors.lastname: Copeland
authors.forename: H
authors.initials: H
authors.lastname: Takahashi
authors.forename: S
authors.initials: S
authors.lastname: Tsuji
authors.forename: D L
authors.initials: DL
authors.lastname: Price
authors.forename: D R
authors.initials: DR
authors.lastname: Borchelt
authors.forename: C A
authors.initials: CA
authors.lastname: Ross
mesh_terms: D000293:Adolescent; D000818:Animals; D001259:Ataxia; D001921:Brain / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism*; D002648:Child; D002819:Chorea; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019578:Multiple System Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D014202:Tremor
chemical_list: D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C095278:atrophin-1