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

Gabriele Schilling, Jonathan D. Wood, Kui Duan, Hilda H. Slunt, Vicky Gonzales, Mitsunori Yamada, Jillian K. Cooper, Russell L. Margolis, Nancy A. Jenkins, Neal G. Copeland, Hitoshi Takahashi, Shoji Tsuji, Donald L. Price, David R. Borchelt, Christopher A. Ross

Research output: Contribution to journalArticlepeer-review

163 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)275-286
Number of pages12
Issue number1
StatePublished - Sep 1999

ASJC Scopus subject areas

  • Neuroscience(all)


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