Maprotiline restores ER homeostasis and rescues neurodegeneration via Histamine Receptor H1 inhibition in retinal ganglion cells.
Maprotiline restores ER homeostasis and rescues neurodegeneration via Histamine Receptor H1 inhibition in retinal ganglion cells.
复制标题
DOI：
10.1038/s41467-022-34682-y
复制
发表时间：
2022-11-10
影响因子：
16.6
通讯作者：
Hu, Yang
中科院分区：
文献类型：
--
作者：
Chen, Wei;Liu, Pingting;Liu, Dong;Huang, Haoliang;Feng, Xue;Fang, Fang;Li, Liang;Wu, Jian;Liu, Liang;Solow-Cordero, David E.;Hu, Yang
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. ER stress is associated with various neurodegenerative diseases. This study found that FDA approved drug, maprotiline, inhibits histamine receptor H1-mediated ER stress and provides significant neuroprotection in mouse glaucoma model.
登录
查看更多内容
影响因子：
6.1
作者：
Fernandes, Kimberly A.;Harder, Jeffrey M.;Fornarola, Laura B.;Freeman, Robert S.;Clark, Abbot F.;Pang, Iok-Hou;John, Simon W. M.;Libby, Richard T.
通讯作者：
Libby, Richard T.
影响因子：
14.8
作者：
Grandjean JMD;Madhavan A;Cech L;Seguinot BO;Paxman RJ;Smith E;Scampavia L;Powers ET;Cooley CB;Plate L;Spicer TP;Kelly JW;Wiseman RL
通讯作者：
Wiseman RL
影响因子：
5.3
作者：
Bruhat, A;Jousse, C;Fafournoux, P
通讯作者：
Fafournoux, P
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
9
作者：
Huang, Haoliang;Miao, Linqing;Hu, Yang
通讯作者：
Hu, Yang