Scarpa, M. et al. (2021) Biased M1 muscarinic receptor mutant mice show accelerated progression of prion neurodegenerative disease. Proceedings of the National Academy of Sciences of the United States of America, 118(50), e2107389118. (doi: 10.1073/pnas.2107389118) (PMID:34893539) (PMCID:PMC8685681)
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Abstract
There are currently no treatments that can slow the progression of neurodegenerative diseases, such as Alzheimer's disease (AD). There is, however, a growing body of evidence that activation of the M1 muscarinic acetylcholine receptor (M1-receptor) can not only restore memory loss in AD patients but in preclinical animal models can also slow neurodegenerative disease progression. The generation of an effective medicine targeting the M1-receptor has however been severely hampered by associated cholinergic adverse responses. By using genetically engineered mouse models that express a G protein-biased M1-receptor, we recently established that M1-receptor mediated adverse responses can be minimized by ensuring activating ligands maintain receptor phosphorylation/arrestin-dependent signaling. Here, we use these same genetic models in concert with murine prion disease, a terminal neurodegenerative disease showing key hallmarks of AD, to establish that phosphorylation/arrestin-dependent signaling delivers neuroprotection that both extends normal animal behavior and prolongs the life span of prion-diseased mice. Our data point to an important neuroprotective property inherent to the M1-receptor and indicate that next generation M1-receptor ligands designed to drive receptor phosphorylation/arrestin-dependent signaling would potentially show low adverse responses while delivering neuroprotection that will slow disease progression.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work is partially funded by a Medical Research Council Industrial CASE studentship (MR/P016693/1; to M.S.), a Medical Research Scotland PhD studentship (PhD-1286-2018; to R.B.), a University of Glasgow Lord Kelvin Adam Smith Fellowship (to S.J.B.), a Medical Research Council MRC Industry Collaboration Agreement (MR/P019366/1; to C.M., M.R., A.B.T., and S.J.B.), a Wellcome Trust Collaborative Award (201529/Z/16/Z; to L.D., G.T., and A.B.T.), an Academy of Medical Sciences Springboard Award (SBF004\1033; to B.D.H.), and an Alzheimer’s Research UK (ARUK) David Hague Early Career Investigator of the Year Award (ARUK-YI2020-002; to S.J.B.). We acknowledge the Biological Services Unit facilities at the Cancer Research UK Beatson Institute (C596/A17196) and the Biological Services at the University of Glasgow. |
| Keywords: | GPCR, phosphorylation, M1 muscarinic acetylcholine receptor, neurodegenerative disease. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Rossi, Dr Mario and Dwomoh, Dr Louis and Molloy, Mr Colin and Jenkins, Mrs Laura and Bradley, Dr Sophie and Hudson, Dr Brian and Strellis, Beth and Tobin, Andrew and Budgett, Rebecca and Hesse, Ms Sarah and Scarpa, Miss Miriam and Milligan, Professor Graeme and Tejeda, Dr Gonzalo and Marsango, Dr Sara |
| Authors: | Scarpa, M., Molloy, C., Jenkins, L., Strellis, B., Budgett, R. F., Hesse, S., Dwomoh, L., Marsango, S., Tejeda, G. S., Rossi, M., Ahmed, Z., Milligan, G., Hudson, B. D., Tobin, A. B., and Bradley, S. J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences College of Medical Veterinary and Life Sciences > School of Life Sciences |
| Journal Name: | Proceedings of the National Academy of Sciences of the United States of America |
| Publisher: | National Academy of Sciences |
| ISSN: | 0027-8424 |
| ISSN (Online): | 1091-6490 |
| Published Online: | 10 December 2021 |
| Copyright Holders: | Copyright © 2021 The Authors |
| First Published: | First published in Proceedings of the National Academy of Sciences of the United States of America 118(50): e2107389118 |
| Publisher Policy: | Reproduced under a Creative Commons License |
| Data DOI: | 10.5525/gla.researchdata.1202 |
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