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Maprotiline restores ER homeostasis and rescues neurodegeneration via Histamine Receptor H1 inhibition in retinal ganglion cells

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机构: [1]Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA [2]High-Throughput Bioscience Center, Stanford UniversitySchool of Medicine, Palo Alto, CA 94305, USA [3]Present address: Multiscale Research Institute of Complex Systems, Fudan University, Shanghai 201203,China [4]Present address: Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha 410011, China [5]Present address:Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
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When the protein or calcium homeostasis of the endoplasmic reticulum (ER) is adversely altered, cells experience ER stress that leads to various diseases including neurodegeneration. Genetic deletion of an ER stress downstream effector, CHOP, significantly protects neuron somata and axons. Here we report that three tricyclic compounds identified through a small-scale high throughput screening using a CHOP promoter-driven luciferase cell-based assay, effectively inhibit ER stress by antagonizing their common target, histamine receptor H1 (HRH1). We further demonstrated that systemic administration of one of these compounds, maprotiline, or CRISPR-mediated retinal ganglion cell (RGC)-specific HRH1 inhibition, delivers considerable neuroprotection of both RGC somata and axons and preservation of visual function in two mouse optic neuropathy models. Finally, we determine that maprotiline restores ER homeostasis by inhibiting HRH1-mediated Ca2+ release from ER. In this work we establish maprotiline as a candidate neuroprotectant and HRH1 as a potential therapeutic target for glaucoma.© 2022. The Author(s).

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大类 | 1 区 综合性期刊
小类 | 1 区 综合性期刊
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大类 | 1 区 综合性期刊
小类 | 1 区 综合性期刊
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Q1 MULTIDISCIPLINARY SCIENCES
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Q1 MULTIDISCIPLINARY SCIENCES

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第一作者机构: [1]Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA [3]Present address: Multiscale Research Institute of Complex Systems, Fudan University, Shanghai 201203,China
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