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Up-regulation of metallothionein gene expression in Parkinsonian astrocytes

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Abstract

The role of glial cells in Parkinson’s disease (PD) is unclear. We have previously reported a striking up-regulation of DnaJB6 heat shock protein in PD substantia nigra astrocytes. Whole genome transcriptome analysis also indicated increased expression of metallothionein genes in substantia nigra and cortex of sporadic PD cases. Metallothioneins are metal-binding proteins in the CNS that are released by astrocytes and associated with neuroprotection. Metallothionein expression was investigated in 18 PD cases and 15 non-PD controls using quantitative real-time polymerase chain reaction (qRT-PCR), in situ hybridisation (ISH) and immunocytochemistry (ICC). We observed a strong increase in the expression of metallothioneins MT1E, MT1F, MT1G, MT1H, MT1M, MT1X and MT2A in both PD nigra and frontal cortex. Expression of LRP2 (megalin), the neuronal metallothionein receptor was also significantly increased. qRT-PCR confirmed metallothionein up-regulation. Astrocytes were found to be the main source of metallothioneins 1 and 2 based on ISH results, and this finding was confirmed by ICC. Our findings demonstrate metallothionein expression by reactive astrocytes in PD nigra and support a neuroprotective role for these cells. The traditional view that nigral astrocytes are non-reactive in PD is clearly incorrect. However, it is possible that astrocytes are themselves affected by the disease process which may explain their comparatively modest and previously overlooked response.

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Acknowledgements

The laboratory work was funded by the UK Parkinson’s Disease Society. Tissue samples were supplied by the UK Parkinson’s Disease Society Tissue Bank at Charing Cross Hospital, Imperial College, London, funded by the Parkinson’s Disease Society of the United Kingdom, registered charity 948776. This study had research ethics committee approval. We express our deepest appreciation to the donors and their families for donating human brain tissue for research.

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Authors and Affiliations

  1. Centre for Neuroscience and Trauma, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Whitechapel, London, E1 2AT, UK

    Gregory J. Michael

  2. The former University Department of Neuropathology, Imperial College, University of London and Hammersmith Hospitals Trust, London, W6 8RF, UK

    Sharmin Esmailzadeh, Linda B. Moran, Lynne Christian, Ronald K. B. Pearce & Manuel B. Graeber

  3. The Brain and Mind Research Institute, University of Sydney, Barnet-Cropper Chair of Brain Tumour Research, 94 Mallett St, Camperdown, Sydney, NSW, 2050, Australia

    Manuel B. Graeber

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  1. Gregory J. Michael
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Correspondence to Manuel B. Graeber.

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Michael, G.J., Esmailzadeh, S., Moran, L.B. et al. Up-regulation of metallothionein gene expression in Parkinsonian astrocytes. Neurogenetics 12, 295–305 (2011). https://doi.org/10.1007/s10048-011-0294-5

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