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

  1. Author:
    Schilling, G.
    Wood, J. D.
    Kui, D. A.
    Slunt, H. H.
    Gonzales, V.
    Yamada, M.
    Cooper, J. K.
    Margolis, R. L.
    Jenkins, N. A.
    Copeland, N. G.
    Takahashi, H.
    Tsuji, S.
    Price, D. L.
    Borchelt, D. R.
    Ross, C. A.

  2. Author Address

    Borchelt DR Johns Hopkins Univ, Sch Med, Dept Pathol Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Dept Pathol Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Dept Psychiat, Div Neurobiol Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Div Neuropathol Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Dept Neurosci Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Dept Neurol Baltimore, MD 21205 USA Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med Baltimore, MD 21205 USA NCI, Mammalian Genet Lab, Ctr Canc Frederick, MD 21702 USA Niigata Univ, Brain Res Inst, Dept Pathol Niigata 951 Japan Niigata Univ, Brain Res Inst, Dept Neurol Niigata 951 Japan
    1. Year: 1999
  2. Journal: Neuron
    1. 24
    2. 1
    3. Pages: 275-286
  4. Type of Article: Article
  1. 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. [References: 60]

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