Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA.
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.
Schilling
G
G
Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Wood
J D
JD
Duan
K
K
Slunt
H H
HH
Gonzales
V
V
Yamada
M
M
Cooper
J K
JK
Margolis
R L
RL
Jenkins
N A
NA
Copeland
N G
NG
Takahashi
H
H
Tsuji
S
S
Price
D L
DL
Borchelt
D R
DR
Ross
C A
CA
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
D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C095278:atrophin-1