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.

The M 1 muscarinic receptor is present in situ as a ligand-regulated mixture of monomers and oligomeric complexes

“…The hippocampal and cortical areas of the brain were isolated from E16 embryos and primary culture carried out as described ( 45 ).…”

β−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives

“…In a related study, Scarpa et al (Scarpa et al, 2021) analyzed knockin mice expressing a phosphorylation-deficient version of the M 1 muscarinic receptor. This mutant receptor couples normally to G q/11 but is deficient in β-arrestin recruitment (Bradley et al, 2020).…”

“…This mutant receptor couples normally to G q/11 but is deficient in β-arrestin recruitment (Bradley et al, 2020). Interestingly, the authors found that mouse prion disease progresses more rapidly in the M 1 receptor mutant mice as compared to WT littermates (Scarpa et al, 2021). Mouse prion disease, a progressive terminal neurodegenerative disease, displays many of the hallmarks of human Alzheimer's disease (AD) (Mallucci et al, 2003).…”

GPCRs in Intracellular Compartments: New Targets for Drug Discovery

“…While in cancer the GPCR–β-arrestin signalosomes play a crucial role in promoting disease progression, in neurodegeneration they are beneficial by slowing down the development of misfolded proteins involved in neurodegenerative disorders. This is the case of the M1 muscarinic receptor and its ability to efficiently signal through β-arrestin [ 111 , 112 ]. Mutant mice with phosphorylation-deficient M1 receptors have more rapid and pronounced misfolded prion-mediated neurodegeneration progression than controls.…”