Dwomoh, L. et al. (2022) M1 muscarinic receptor activation reduces the molecular pathology and slows the progression of prion-mediated neurodegenerative disease. Science Signaling, 15(760), eabm3720. (doi: 10.1126/scisignal.abm3720) (PMID:36378750)
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Abstract
Many dementias are propagated through the spread of “prion-like” misfolded proteins. This includes prion diseases themselves (such as Creutzfeldt-Jakob disease) and Alzheimer’s disease (AD), for which no treatments are available to slow or stop progression. The M1 acetylcholine muscarinic receptor (M1 receptor) is abundant in the brain, and its activity promotes cognitive function in preclinical models and in patients with AD. Here, we investigated whether activation of the M1 receptor might slow the progression of neurodegeneration associated with prion-like misfolded protein in a mouse model of prion disease. Proteomic and transcriptomic analysis of the hippocampus revealed that this model had a molecular profile that was similar to that of human neurodegenerative diseases, including AD. Chronic enhancement of the activity of the M1 receptor with the positive allosteric modulator (PAM) VU0486846 reduced the abundance of prion-induced molecular markers of neuroinflammation and mitochondrial dysregulation in the hippocampus and normalized the abundance of those associated with neurotransmission, including synaptic and postsynaptic signaling components. PAM treatment of prion-infected mice prolonged survival and maintained cognitive function. Thus, allosteric activation of M1 receptors may reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Rossi, Dr Mario and Tobin, Andrew and Herzyk, Dr Pawel and Dwomoh, Dr Louis and Molloy, Mr Colin and Scarpa, Miss Miriam and Khajehali, Dr Elham and Bradley, Dr Sophie |
| Authors: | Dwomoh, L., Rossi, M., Scarpa, M., Khajehali, E., Molloy, C., Herzyk, P., Mistry, S. N., Bottrill, A. R., Sexton, P. M., Christopoulos, A., Conn, J., Lindsley, C. W., Bradley, S. J., and Tobin, A. B. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Science Signaling |
| Publisher: | American Association for the Advancement of Science |
| ISSN: | 1945-0877 |
| ISSN (Online): | 1937-9145 |
| Copyright Holders: | Copyright © 2022 The Authors |
| First Published: | First published in Science Signaling 15(760): eabm3720 |
| Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
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