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Phosphorylation of the M1 muscarinic acetylcholine receptor protects from neurodegenerative disease
Thursday, 09/16/2021 @ 9:00 AM - EST
- Dr. Miriam Scarpa -
- The University Of Glasgow -
- Glasgow, Scotland -
Abstract
The M1 muscarinic acetylcholine receptor (M1 mAChR) plays a crucial role in learning and memory and is a validated drug target for the treatment of Alzheimer’s disease (AD). Pharmacological activation of the M1 mAChR can improve memory in AD patients but has also been shown to modify neurodegenerative disease progression in preclinical mouse models. By employing a novel transgenic mouse model expressing a phosphorylation-deficient mutant M1 mAChR (M1-PD), we explored the role of M1 mAChR phosphorylation-dependent pathways in the disease modification potential of the receptor. By combining the M1-PD transgenic mice with prion neurodegenerative disease, a model of terminal neurodegeneration that shares key disease hallmarks with AD, we revealed that the M1 mAChR has an inherent neuroprotective mechanism that is dependent on its phosphorylation.
M1-PD mice with prion disease showed significantly accelerated disease progression compared to wild-type mice, which was evident in the earlier onset of symptoms and hippocampal dysfunction and the up-regulation of markers of disease and neuroinflammation. These findings have important implications for the development of new drug treatments for neurodegenerative diseases, especially M1 mAChR ligands that maintain receptor phosphorylation will more likely deliver neuroprotection that could not only improve memory symptoms but also modify disease. Further, given the parallels between mouse prion disease and AD, the inherent M1 mAChR-mediated neuroprotection could also be relevant for protection against other human neurodegenerative conditions.
About Miriam Scarpa
Miriam Scarpa is a final year Ph.D. researcher at the University of Glasgow Centre for Translational Pharmacology, funded by an MRC-iCASE studentship in collaboration with Eli Lilly and Company and supervised by Dr. Sophie Bradley, Prof Andrew Tobin, and Dr. Zeshan Ahmed. Her research investigates G protein-coupled receptors (GPCRs) as drug targets for the symptomatic and disease-modifying treatment of neurodegenerative conditions, with a particular focus on the M1 muscarinic acetylcholine receptor.
Author list and affiliations
Miriam Scarpa1, Colin Molloy1, Laura Jenkins1, Bethany Strellis1, Rebecca Budgett1, Sarah Hesse1, Louis Dwomoh1, Sara Marsango1, Gonzalo Tejeda1, Mario Rossi1, Zeshan Ahmed2, Graeme Milligan1, Brian D. Hudson1, Andrew B. Tobin1, and Sophie J. Bradley1.
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1 The Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
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2 Eli Lilly & Co, Neuroscience Discovery, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK.
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