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Synphilin-1 attenuates neuronal degeneration in the A53T alpha-synuclein transgenic mouse model

  1. Author:
    Smith, W. W.
    Liu, Z. H.
    Liang, Y. D.
    Masuda, N.
    Swing, D. A.
    Jenkins, N. A.
    Copeland, N. G.
    Troncoso, J. C.
    Pletnikov, M.
    Dawson, T. M.
    Martin, L. J.
    Moran, T. H.
    Lee, M. K.
    Borchelt, D. R.
    Ross, C. A.

  2. Author Address

    [Smith, Wanli W.; Liu, Zhaohui] Univ Maryland, Dept Pharmaceut Sci, Sch Pharm, Baltimore, MD 21201 USA. [Smith, Wanli W.; Liu, Zhaohui; Liang, Yideng; Masuda, Naoki; Pletnikov, Mikhail; Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Div Neurobiol, Baltimore, MD 21287 USA. [Pletnikov, Mikhail; Dawson, Ted M.; Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA. [Dawson, Ted M.; Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. [Troncoso, Juan C.; Martin, Lee J.; Borchelt, David R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. [Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Dept Pharmacol, Baltimore, MD 21287 USA. [Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Neuroregenerat Program, Inst Cell Engn, Baltimore, MD 21287 USA. [Dawson, Ted M.] Johns Hopkins Univ, Sch Med, Stem Cell Program, Inst Cell Engn, Baltimore, MD 21287 USA. [Pletnikov, Mikhail; Ross, Christopher A.] Johns Hopkins Univ, Sch Med, Cellular & Mol Med Program, Baltimore, MD 21287 USA. [Moran, Timothy H.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Div Behav Neurosci, Baltimore, MD 21287 USA. [Swing, Debbie A.; Jenkins, Nancy A.; Copeland, Neal G.] NCI, Mouse Canc Genet Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. [Lee, Michael K.] Univ Minnesota, Dept Neurosci, Minneapolis, MN 55455 USA.;Smith, WW, Univ Maryland, Dept Pharmaceut Sci, Sch Pharm, 20 Penn St, Baltimore, MD 21201 USA.;wsmith@rx.umaryland.edu caross@jhu.edu
    1. Year: 2010
    2. Date: Jun
  2. Journal: Human Molecular Genetics
    1. 19
    2. 11
    3. Pages: 2087-2098
  4. Type of Article: Article
  5. ISSN: 0964-6906
  1. Abstract:

    Genetic alterations in alpha-synuclein cause autosomal dominant familial Parkinsonism and may contribute to sporadic Parkinson's disease (PD). Synphilin-1 is an alpha-synuclein-interacting protein, with implications in PD pathogenesis related to protein aggregation. Currently, the in vivo role of synphilin-1 in alpha-synuclein-linked pathogenesis is not fully understood. Using the mouse prion protein promoter, we generated synphilin-1 transgenic mice, which did not display PD-like phenotypes. However, synphilin-1/A53T alpha-synuclein double-transgenic mice survived longer than A53T alpha-synuclein single-transgenic mice. There were attenuated A53T alpha-synuclein-induced motor abnormalities and decreased astroglial reaction and neuronal degeneration in brains in double-transgenic mice. Overexpression of synphilin-1 decreased caspase-3 activation, increased beclin-1 and LC3 II expression and promoted formation of aggresome-like structures, suggesting that synphilin-1 alters multiple cellular pathways to protect against neuronal degeneration. These studies demonstrate that synphilin-1 can diminish the severity of alpha-synucleinopathy and play a neuroprotective role against A53T alpha-synuclein toxicity in vivo.

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External Sources

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  2. DOI: 10.1093/hmg/ddq086
  3. View record in Web of Science®
  4. WOS: 000277448500001

Library Notes

  1. Fiscal Year: FY2009-2010
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