气候变化领域集成服务门户(CCPortal): Biased M1 muscarinic receptor mutant mice show accelerated progression of prion neurodegenerative disease

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DOI	10.1073/pnas.2107389118
	Biased M1 muscarinic receptor mutant mice show accelerated progression of prion neurodegenerative disease
	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.; Bradley S.J.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:50
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	GPCR; M1 muscarinic acetylcholine receptor; Neurodegenerative disease; Phosphorylation
语种	英语
scopus关键词	muscarinic M1 receptor; retina S antigen; guanine nucleotide binding protein alpha subunit; muscarinic M1 receptor; animal experiment; animal model; animal tissue; Article; bioaccumulation; carboxy terminal sequence; controlled study; disease exacerbation; female; lifespan; male; mouse; nonhuman; prion disease; protein expression; protein phosphorylation; signal transduction; survival time; animal; cell culture; gene expression regulation; genetics; knockout mouse; metabolism; nerve cell; pathology; physiology; prion disease; Animals; Cells, Cultured; Gene Expression Regulation; GTP-Binding Protein alpha Subunits, Gq-G11; Mice; Mice, Knockout; Neurons; Prion Diseases; Receptor, Muscarinic M1; Signal Transduction
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/250932
作者单位	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, United Kingdom; Neuroscience Next Generation Therapeutics (NGTx), Eli Lilly and Company, Cambridge, MA 02142, United Kingdom
推荐引用方式 GB/T 7714	Scarpa M.,Molloy C.,Jenkins L.,et al. Biased M1 muscarinic receptor mutant mice show accelerated progression of prion neurodegenerative disease[J],2021,118(50).
APA	Scarpa M..,Molloy C..,Jenkins L..,Strellis B..,Budgett R.F..,...&Bradley S.J..(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).
MLA	Scarpa M.,et al."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(2021).