A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum resident proteome.

Hot Off the Press – April 30, 2021

Published in Cell Reports by Mark Henderson and Kathleen Trychta, et al.

In the paper by Henderson et al., we developed a high throughput screen to identify molecules that can stabilize protein homeostasis inside of cells (brain, muscle, liver, etc) during pathological states. The screen was based off a cellular phenomenon called “exodosis” that was discovered in my lab at the NIDA IRP. Through collaboration with NCATS and other intramural and extramural collaborators, we identified both FDA approved drugs (e.g. bromocriptine) and novel molecules that can prevent exodosis in a variety of disease states where exodosis occurs (stroke, diabetes, Wolfram syndrome and obesity). We have also observed exodosis in models of substance abuse where we hope to prevent acute toxicity associated with methamphetamine and MDMA overdosing. This is part of a story that has originated at the NIDA IRP and continues to expand and move towards new therapeutics for substance abuse and other diseases.

Publication Information

Henderson, Mark J; Trychta, Kathleen A; Yang, Shyh-Ming; Bäck, Susanne; Yasgar, Adam; Wires, Emily S; Danchik, Carina; Yan, Xiaokang; Yano, Hideaki; Shi, Lei; Wu, Kuo-Jen; Wang, Amy Q; Tao, Dingyin; ohalmi, Gergely Zahoránszky-KH; Hu, Xin; Xu, Xin; Maloney, David; Zakharov, Alexey V; Rai, Ganesha; Urano, Fumihiko; Airavaara, Mikko; Gavrilova, Oksana; Jadhav, Ajit; Wang, Yun; Simeonov, Anton; Harvey, Brandon K

A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome Journal Article

In: Cell Reports, vol. 35, no. 4, 2021, ISBN: 2211-1247.

Abstract | Links

@article{Henderson:2021aa,

title = {A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome},

author = {Mark J Henderson and Kathleen A Trychta and Shyh-Ming Yang and Susanne Bäck and Adam Yasgar and Emily S Wires and Carina Danchik and Xiaokang Yan and Hideaki Yano and Lei Shi and Kuo-Jen Wu and Amy Q Wang and Dingyin Tao and Gergely Zahoránszky-K{H o}halmi and Xin Hu and Xin Xu and David Maloney and Alexey V Zakharov and Ganesha Rai and Fumihiko Urano and Mikko Airavaara and Oksana Gavrilova and Ajit Jadhav and Yun Wang and Anton Simeonov and Brandon K Harvey},

url = {https://pubmed.ncbi.nlm.nih.gov/33910017/},

doi = {10.1016/j.celrep.2021.109040},

isbn = {2211-1247},

year  = {2021},

date = {2021-04-27},

urldate = {2021-04-27},

booktitle = {Cell Reports},

journal = {Cell Reports},

volume = {35},

number = {4},

publisher = {Elsevier},

abstract = {Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. Bromocriptine elicits protective effects in cell-based models of exodosis as well as in vivo models of stroke and diabetes. Bromocriptine analogs with reduced dopamine receptor activity retain similar efficacy in stabilizing the ER proteome, indicating a non-canonical mechanism of action. This study describes a strategic approach to identify small-molecule drugs capable of improving ER proteostasis in human disease conditions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}