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Proteasomal inhibition causes loss of nigral tyrosine hydroxylase neurons

Authors

  • Anthony H. V. Schapira MD, DSc, FMedSci,

    Corresponding author
    1. University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom
    2. Institute of Neurology, University College London, London, United Kingdom
    • University Department of Clinical Neurosciences, Royal Free and University College Medical School, Hampstead Campus, Rowland Hill Street, London NW3 2PH, United Kingdom
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  • Michael W. J. Cleeter PhD,

    1. University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom
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  • John R. Muddle,

    1. University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom
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  • Jane M. Workman BSc(Hons), FIBMS,

    1. University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom
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  • J. Mark Cooper PhD,

    1. University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom
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  • Rosalind H. M. King PhD

    1. University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom
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Abstract

Dysfunction of the ubiquitin-proteasomal system (UPS) has been implicated in the pathogenesis of Parkinson's disease. The systemic administration of UPS inhibitors has been reported to induce nigrostriatal cell death and model Parkinson's disease pathology in rodents. We administered a synthetic, specific UPS inhibitor (PSI) subcutaneously to rats and quantified substantia nigral tyrosine hydroxylase–positive dopaminergic neurons by stereology. PSI caused a 15% decrease in UPS activity at 2 weeks and a 42% reduction in substantia nigra pars compacta tyrosine hydroxylase–positive neurons at 8 weeks. Systemic inhibition of the UPS warrants further evaluation as a means to model Parkinson's disease. Ann Neurol 2006;60:253–255

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