神经保护
逮捕
生物
受体
神经科学
信号转导
细胞生物学
G蛋白偶联受体
遗传学
作者
Miriam Scarpa,Colin Molloy,Laura Jenkins,Bethany Strellis,Rebecca F. Budgett,Sarah Hesse,Louis Dwomoh,Sara Marsango,Gonzalo S. Tejeda,Mario Rossi,Zeshan Ahmed,Graeme Milligan,Brian D. Hudson,Andrew B. Tobin,Sophie J. Bradley
标识
DOI:10.1073/pnas.2107389118
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.
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