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

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.

SUBMITTER: Scarpa M

PROVIDER: S-EPMC8685681 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Scarpa Miriam M Molloy Colin C Jenkins Laura L Strellis Bethany B Budgett Rebecca F RF Hesse Sarah S Dwomoh Louis L Marsango Sara S Tejeda Gonzalo S GS Rossi Mario M Ahmed Zeshan Z Milligan Graeme G Hudson Brian D BD Tobin Andrew B AB Bradley Sophie J SJ

Proceedings of the National Academy of Sciences of the United States of America 20211201 50

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 ch ...[more]

PMID: 34893539

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Project description:Purpose: evaluation of the neuroprotective effects of VU846 compound, a positive allosteric modulator highly specific for the M1 muscarinic receptor, using the Next-generation sequencing (NGS) technology in a context of neurodegeneration induced by prion disease. Methods: Tg37 hemizygous mice at 3 to 4 weeks were inoculated with either the Rocky Mountain Laboratory (RML) scrapie prion brain homogenate, causative of the neurodegeneration, or normal brain homogenate for control purposes. Mice were also daily injected with either the M1 specific positive allosteric modulator VU836 or vehicle. The drug treatment started at 7week post brain homogenate inoculations (wpi) and 11wpi. The hippocampi from 3 mice of each group (control + vehicle, control + VU846, prion + vehicle and prion + VU846) were subject to tot RNA extraction. Raw reads were then converted into Fastq format, mapped to the “mouse-mm10” genome using HISAT2 (Galaxy Version 2.1.0) and processed with the StringTie (Galaxy Version 1.3.3.2) for assembling and quantification. Differential gene expression comparisons were performed with DESeq2 statistical tool (Galaxy Version 2.11.40.2) and data further analysed with two online software suites, Gene Ontology Panther (http://www.pantherdb.org/) and Pathway Studio (www.pathwaystudio.com). Results: we use the bioinformatic tool Pathway Studio (www.pathwaystudio.com) to quantitatively assesses the changes in the transcriptome with gene functions reported in the literature to assign an actication score. Strikingly, up and down regulation of genes changed by prion disease promote neuroinflammation and Alzheimer’s disease (AD) (positive activation scores), whereas the M1R specific positive allosteric modulator VU846 treatment modified the expression of genes to inhibit the neuroinflammatory and neurodegenerative processes directly associated with AD (negative activation score). Among these are genes associated with the complement system, microglia and astrocyte activation. Furthermore, consistent with the notion that neuroinflammatory pathways were activated in prion disease and diminished by VU846, the GO Pathway analysis revealed enrichment of genes in pathways such as the complement cascade and chemokine/cytokine signalling. Conversely, a group of genes that were down-regulated in prion disease were transcribed at significantly higher levels in the prion-effect of animals treated with VU846. These genes were strongly associated with synaptic plasticity, learning and memory, cognition and synaptic transmission by the GO Pathway analysis. Conclusions: These data point to the possibility that specific features of neuroinflammation and disease-adaptation may be directly regulated by M1-receptor activity strongly reinforcing the concept that pharmaceutically targeting M1 muscarinic receptor is neuroprotective and it might lead to the development of new treatments of Alzheimer’s like neurodegenerative diseases.

Dataset Information

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

Publications

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

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