Biased M1 muscarinic receptor mutant mice show accelerated progression of prion neurodegenerative disease

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, Bethany 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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
174202MICA Pharmacological, molecular and cellular mechanisms of muscarinic slowing (modification) of neurodegenerative disease.Andrew TobinMedical Research Council (MRC)MR/P019366/1Institute of Molecular, Cell & Systems Biology
173304Collaborative Network to Define the Molecular Determinants of G Protein Coupled Receptor Clinical EfficacyAndrew TobinWellcome Trust (WELLCOTR)201529/Z/16/ZMCSB - Molecular Pharmacology
304366Hudson AMS SpringboardBrian HudsonAcademy of Medical Sciences (ACMEDSCI)SBF0041033Institute of Molecular, Cell & Systems Biology
314130ARUK David Hague AwardSophie BradleyAlzheimer`s Research UK (ALZRESUK)ARUK-YI2020-002Institute of Molecular, Cell & Systems Biology