Precision genetic cellular models identify therapies protective against ER stress

Irina V Lebedeva,Sunil Sahdeo,David B Goldstein,Gunaretnam Rajagopal,Yi-Fan Lu,Matthew B Harms,Anuli Anyanwu-Ofili,Michael J Boland,Michelle V Wagner,Jehangir S Wadia

doi:10.1038/s41419-021-04045-4

Abstract

Rare monogenic disorders often share molecular etiologies involved in the pathogenesis of common diseases. Congenital disorders of glycosylation (CDG) and deglycosylation (CDDG) are rare pediatric disorders with symptoms that range from mild to life threatening. A biological mechanism shared among CDG and CDDG as well as more common neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis, is endoplasmic reticulum (ER) stress. We developed isogenic human cellular models of two types of CDG and the only known CDDG to discover drugs that can alleviate ER stress. Systematic phenotyping confirmed ER stress and identified elevated autophagy among other phenotypes in each model. We screened 1049 compounds and scored their ability to correct aberrant morphology in each model using an agnostic cell-painting assay based on >300 cellular features. This primary screen identified multiple compounds able to correct morphological phenotypes. Independent validation shows they also correct cellular phenotypes and alleviate each of the ER stress markers identified in each model. Many of the active compounds are associated with microtubule dynamics, which points to new therapeutic opportunities for both rare and more common disorders presenting with ER stress, such as Alzheimer’s disease and amyotrophic lateral sclerosis.

Highlights

The study of rare monogenic disorders has yielded a number of insights into the molecular mechanisms underlying the pathobiology of more common diseases [1, 2]
endoplasmic reticulum (ER) stress has been implicated in diseases including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS) [5]. This suggests that therapeutic agents that ameliorate the effects of ER stress in monogenic disorders could have benefits across a broad range of disorders. Screens to identify such agents in the context of complex neurodegenerative diseases are challenging to implement; the etiology of a number of monogenic diseases is in large part attributed to ER stress including the congenital disorders of glycosylation (CDG) and deglycosylation (CDDG) [6,7,8]
A central challenge to the development of novel therapies is the availability of screenable models that focus on disease-relevant phenotypes

Summary

Introduction

The study of rare monogenic disorders has yielded a number of insights into the molecular mechanisms underlying the pathobiology of more common diseases [1, 2]. Numerous diseases affecting both the central and peripheral nervous system involve elevated endoplasmic reticulum (ER) stress [3, 4]. ER stress has been implicated in diseases including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS) [5] This suggests that therapeutic agents that ameliorate the effects of ER stress in monogenic disorders could have benefits across a broad range of disorders. Mutations in DPAGT1, which encodes the target of the well-known ER stress inducer tunicamycin [11], result in another CDG with systemic phenotypes [12, 13]

Methods

Results

Conclusion