A humanized Gs-coupled DREADD for circuit and behavior modulation.

IF 4.2 3区医学 Q2 NEUROSCIENCES

Frontiers in Cellular Neuroscience Pub Date : 2025-04-09 eCollection Date: 2025-01-01 DOI:10.3389/fncel.2025.1577117

Qi Zhang, Ruiqi Wang, Liang Zhang, Mengqi Li, Jianbang Lin, Xiaoyang Lu, Yixuan Tian, Yunping Lin, Taian Liu, Yefei Chen, Yuantao Li, Jun Cao, Qiang Wu, Jinhui Wang, Zhonghua Lu, Zexuan Hong

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引用次数: 0

Abstract

Designer receptors exclusively activated by designer drugs (DREADDs) play important roles in neuroscience research and show great promise for future clinical interventions in neurological diseases. The Gs-coupled DREADD, rM3Ds, modulates excitability in neuron subsets that are sensitive to downstream effectors of Gs protein. However, given the non-human nature of the rM3Ds backbone, risks about potential immunogenicity and tolerability exist when considering clinical translation. Here, we report the development of a whole sequence-humanized Gs-coupled DREADD, hM3Ds. We found that hM3Ds has a comparable DREADD ligand response profile to rM3Ds. We then selectively expressed hM3Ds in D1 medium spiny neurons (D1-MSNs) and found that hM3Ds was able to activate the D1-MSNs-mediated basal ganglia direct pathway and alleviate Parkinsonian phenotypes in a Parkinson's disease mouse model. In conclusion, this engineered humanized Gs-coupled DREADD is suitable as an effective, and likely safer, DREADD tool for both research and future clinical applications.

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用于电路和行为调制的人性化gs耦合DREADD。

由设计物药物激活的设计物受体在神经科学研究中发挥着重要的作用，并在未来的神经系统疾病的临床干预中显示出巨大的希望。Gs偶联的DREADD （rM3Ds）可调节对Gs蛋白下游效应物敏感的神经元亚群的兴奋性。然而，考虑到rM3Ds骨架的非人类性质，在考虑临床转化时存在潜在的免疫原性和耐受性风险。在这里，我们报道了一个全序列的发展-人性化gs耦合的DREADD， hM3Ds。我们发现hM3Ds与rM3Ds具有相似的DREADD配体响应谱。然后，我们在D1中棘神经元（D1- msns）中选择性表达hM3Ds，发现hM3Ds能够激活D1- msns介导的基底节区直接通路，并减轻帕金森病小鼠模型中的帕金森表型。总之，这种工程人源化gs偶联的DREADD是一种有效的、可能更安全的DREADD工具，适用于研究和未来的临床应用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Frontiers in Cellular Neuroscience NEUROSCIENCES-

CiteScore

7.90

自引率

3.80%

发文量

627

审稿时长

6-12 weeks

期刊介绍： Frontiers in Cellular Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the cellular mechanisms underlying cell function in the nervous system across all species. Specialty Chief Editors Egidio D‘Angelo at the University of Pavia and Christian Hansel at the University of Chicago are supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.