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Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson’s Disease

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Abstract

Neuroinflammation is thought to contribute to cell death in neurodegenerative disorders, but the factors involved in the inflammatory process are not completely understood. Proteinase-activated receptor-2 (PAR2) expression in brain is increased in Alzheimer’s disease and multiple sclerosis, but the status of PAR2 in Parkinson’s disease is unknown. This study examined expression of PAR2 and endogenous proteinase activators (trypsin-2, mast cell tryptase) and proteinase inhibitors (serpin-A5, serpin-A13) in areas vulnerable and resistant to neurodegeneration in Parkinson’s disease at different Braak α-synuclein stages of the disease in post-mortem brain. In normal aged brain, expression of PAR-2, trypsin-2, and serpin-A5 and serpin-A13 was found in neurons and microglia, and alterations in the amount of immunoreactivity for these proteins were found in some brain regions. Namely, there was a decrease in neurons positive for serpin-A5 in the dorsal motor nucleus, and serpin-A13 expression was reduced in the locus coeruleus and primary motor cortex, while expression of PAR2, trypsin-2 and both serpins was reduced in neurons within the substantia nigra. There was an increased number of microglia that expressed serpin-A5 in the dorsal motor nucleus of vagus and elevated numbers of microglia that expressed serpin-A13 in the substantia nigra of late Parkinson’s disease cases. The number of microglia that expressed trypsin-2 increased in primary motor cortex of incidental Lewy body disease cases. Analysis of Parkinson’s disease cases alone indicated that serpin-A5 and serpin-A13, and trypsin-2 expression in midbrain and cerebral cortex was different in cases with a high incidence of l-DOPA-induced dyskinesia and psychosis compared to those with low levels of these treatment-induced side effects. This study showed that there was altered expression in brain of PAR2 and some proteins that can control its function in Parkinson’s disease. Given the role of PAR2 in neuroinflammation, drugs that mitigate these changes may be neuroprotective when administered to patients with Parkinson’s disease.

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Acknowledgments

Tissue samples and associated clinical and neuropathological data were supplied by the Parkinson’s UK Tissue Bank, funded by Parkinson’s UK, a charity registered in England and Wales (258197) and in Scotland (SC037554). Tissue with a short post-mortem interval that was used in preliminary experiments was provided by the Brain and Body Donation Program, Arizona, USA.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Funding

The Michael J. Fox Foundation and the Cure Parkinson’s Trust funded this work.

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Authors and Affiliations

  1. Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK

    Michael J. Hurley, Pascal F. Durrenberger & David T. Dexter

  2. Neuropathology Unit, Division of Brain Sciences, Department of Medicine, Imperial College London, Charing Cross Campus, St Dunstan’s Road, London, W6 8RP, UK

    Steve M. Gentleman

  3. Immunopharmacology Group, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, UK

    Andrew F. Walls

Authors
  1. Michael J. Hurley
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  2. Pascal F. Durrenberger
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  4. Andrew F. Walls
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Correspondence to Michael J. Hurley.

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Hurley, M.J., Durrenberger, P.F., Gentleman, S.M. et al. Altered Expression of Brain Proteinase-Activated Receptor-2, Trypsin-2 and Serpin Proteinase Inhibitors in Parkinson’s Disease. J Mol Neurosci 57, 48–62 (2015). https://doi.org/10.1007/s12031-015-0576-8

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  • DOI: https://doi.org/10.1007/s12031-015-0576-8

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