Muscarinic receptor binding changes in postmortem Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a devastating disorder, affecting approximately 2% of people aged 60 and above. It is marked by progressive neurodegeneration that has long been known to impact dopaminergic cells and circuits, but more recently the acetylcholine system has also been implicated in the complex aetiology and symptomatology of the disease. While broad changes in cholinergic markers have been described, insight into the contribution of specific acetylcholine receptors is less clear. To address this important unknown, in this study we performed [3H] pirenzepine, [3H] 4DAMP, and [3H] AF-DX 384 in situ radioligand binding on postmortem tissues from Brodmann’s area 6, 9, 46, and the caudate putamen, from PD and matched controls to detect muscarinic M1, M3, and M1/2/4 receptors, respectively. We found no difference in [3H] pirenzepine binding between PD and controls across all regions assessed. [3H] 4DAMP binding was found to be higher in PD CPu and BA9 than in controls. [3H] AF-DX 384 was higher in BA9 of PD compared with controls. In sum, we show selective increase in M3 receptors in cortical and subcortical regions, as well as increased M2/M4 in cortical area BA9, which together support a role for cholinergic dysfunction in PD.

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Acknowledgements

We would like to thank the families of the subjects for donating the tissue used in these studies. Human brain tissues were received from the Victorian Brain Bank Network, supported by The Florey Institute of Neuroscience and Mental Health, The Alfred and the Victorian Forensic Institute of Medicine, and funded by Australia’s National Health & Medical Research Council and Parkinson’s Victoria. We would also like to thank Andrew Gibbons, Natalie Thomas, and Won Je Jeon for their input on the radioligand binding methodology.

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Correspondence to Caitlin McOmish.

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Funding

CEM was supported by an NHMRC overseas biomedical research fellowship (APP628906), a Brain and Behavior Research Foundation Young Investigator Award (19543), while these studies were being performed. BD is an NHMRC Senior Research Fellow (APP1002240). This work was supported in part by NHMRC Project Grants (APP1045619, APP628699, and APP1066144), the Victorian Government’s Operational Infrastructure Support, and the Rebecca Cooper Medical Research Foundation. ES was supported by an ARC future fellowship (FT100100689). The funding sources were not involved in the study design; in the collection, the analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

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The authors have no conflicts of interest to declare.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed, and all procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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McOmish, C., Pavey, G., McLean, C. et al. Muscarinic receptor binding changes in postmortem Parkinson’s disease. J Neural Transm 124, 227–236 (2017). https://doi.org/10.1007/s00702-016-1629-z

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Keywords

  • Parkinson’s disease
  • Acetylcholine
  • Muscarinic receptor
  • Postmortem
  • Human