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

  • Nat Commun. 2022 Nov 10;13(1):6796. doi: 10.1038/s41467-022-34682-y.
Wei Chen  #  1  2 ,  Pingting Liu  #  1 ,  Dong Liu  1 ,  Haoliang Huang  1 ,  Xue Feng  1 ,  Fang Fang  1  3 ,  Liang Li  1 ,  Jian Wu  1  4 ,  Liang Liu  1 ,  David E Solow-Cordero  5 ,  Yang Hu  6
Affiliations
  • 1. Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA.
  • 2. Multiscale Research Institute of Complex Systems, Fudan University, Shanghai, 201203, China.
  • 3. Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
  • 4. Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
  • 5. High-Throughput Bioscience Center, Stanford University School of Medicine, Palo Alto, CA, 94305, USA.
  • 6. Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA. [email protected].
  • # Contributed equally.
PMID: 36357388 DOI: 10.1038/s41467-022-34682-y
Abstract

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.

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