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Abnormal Phosphorylation of Synapsin I Predicts a Neuronal Transmission Impairment in the R6/2 Huntington's Disease Transgenic Mice

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Abstract

Motor and cognitive deficits in Huntington's disease (HD) are likely caused by progressive neuronal dysfunction preceding neuronal cell death. Synapsin I is one of the major phosphoproteins regulating neurotransmitter release. We report here an abnormal phosphorylation state of synapsin I in the striatum and the cerebral cortex of R6/2 transgenic mice expressing the HD mutation. These changes are mostly characterized by an early overphosphorylation at sites 3–5, whereas phosphorylation at site 1 remains unchanged and at site 6 becomes reduced only close to the end stage of the disease. Such changes do not result from modification in protein expression levels. However, we show a decreased expression of the calcineurin regulatory subunit-B, which may contribute to an imbalance between kinase and phosphatase activities. Together the results suggest that an early impairment in synapsin phosphorylation–dephosphorylation may alter synaptic vesicle trafficking and lead to defective neurotransmission in HD.

References (62)

  • E.G. McGeer et al.

    Kainate-induced degeneration of neostriatal neurons: dependency upon corticostriatal tract

    Brain Res.

    (1978)
  • L. Menalled et al.

    Decrease in striatal enkephalin mRNA in mouse models of Huntington's disease

    Exp. Neurol.

    (2000)
  • A.J. Morton et al.

    Mice transgenic for the human Huntington's disease mutation have reduced sensitivity to kainic acid toxicity

    Brain Res. Bull.

    (2000)
  • L.R. Orlando et al.

    The role of group I and group II metabotropic glutamate receptors in modulation of striatal NMDA and quinolinic acid toxicity

    Exp. Neurol.

    (2001)
  • F. Perez-Severiano et al.

    Striatal oxidative damage parallels the expression of a neurological phenotype in mice transgenic for the mutation of Huntington's disease

    Brain Res.

    (2000)
  • W. Schiebler et al.

    Characterization of synapsin I binding to small synaptic vesicles

    J. Biol. Chem.

    (1986)
  • M. Stanciu et al.

    Prolonged nuclear retention of activated extracellular signal-regulated protein kinase promotes cell death generated by oxidative toxicity or proteasome inhibition in a neuronal cell line

    J. Biol. Chem.

    (2002)
  • M. Stanciu et al.

    Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures

    J. Biol. Chem.

    (2000)
  • F. Valtorta et al.

    Effects of the neuronal phosphoprotein synapsin I on actin polymerization. I. Evidence for a phosphorylation-dependent nucleating effect

    J. Biol. Chem.

    (1992)
  • M. Bahler et al.

    Synapsin I bundles F-actin in a phosphorylation-dependent manner

    Nature

    (1987)
  • A.J. Baines et al.

    Synapsin I is a microtubule-bundling protein

    Nature

    (1986)
  • F. Benfenati et al.

    Time-resolved fluorescence study of the neuron-specific phosphoprotein synapsin. I. Evidence for phosphorylation-dependent conformational changes

    J. Biol. Chem.

    (1990)
  • A.F. Bennett et al.

    Bundling of microtubules by synapsin. 1. Characterization of bundling and interaction of distinct sites in synapsin 1 head and tail domains with different sites in tubulin

    Eur. J. Biochem.

    (1992)
  • J.A. Bibb et al.

    Severe deficiencies in dopamine signaling in presymptomatic Huntington's disease mice

    Proc. Natl. Acad. Sci. USA

    (2000)
  • K. Biziere et al.

    Effects of cortical ablation on the neurotoxicity and receptor binding of kainic acid in striatum

    J. Neurosci. Res.

    (1979)
  • R.J. Carter et al.

    Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation

    J. Neurosci.

    (1999)
  • J.H. Cha et al.

    Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease

    Phil. Trans. R. Soc. Lond. B Biol. Sci.

    (1999)
  • J.H. Cha et al.

    Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene

    Proc. Natl. Acad. Sci. USA

    (1998)
  • P. Chi et al.

    Synapsin dispersion and reclustering during synaptic activity

    Nature Neurosci.

    (2001)
  • A.J. Czernik et al.

    Production of phosphorylation state-specific antibodies

    Methods Enzymol.

    (1991)
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    To whom correspondence should be addressed at Division of Medical and Molecular Genetics, GKT School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK. Fax: 020 7955 4444. E-mail: [email protected].

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