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Neuron. 1999 Sep;24(1):275-86.

Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA.

Author information

1
Department of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

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.

PMID:
10677044
DOI:
10.1016/s0896-6273(00)80839-9
[Indexed for MEDLINE]
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