Precision genetic cellular models identify therapies protective against ER stress

• Published in: Cell death & disease Vol. 12; no. 8; pp. 770 - 11
• Main Authors: Lebedeva, Irina V., Wagner, Michelle V., Sahdeo, Sunil, Lu, Yi-Fan, Anyanwu-Ofili, Anuli, Harms, Matthew B., Wadia, Jehangir S., Rajagopal, Gunaretnam, Boland, Michael J., Goldstein, David B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.08.2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 14/1; 14/63; 38/44; 38/47; 38/77; 631/154/1435/2163; 631/80/2373; 631/80/86/2366; 692/699/375/366; 82/80; 96/95; Activating Transcription Factor 6 - metabolism; Alzheimer's disease; Amyotrophic lateral sclerosis; Antibodies; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line; Cell Proliferation - drug effects; Cell Shape - drug effects; Congenital Disorders of Glycosylation - pathology; Cytology; Deglycosylation; Drug Evaluation, Preclinical; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - genetics; Glycosylation; Humans; Immunology; Life Sciences; Models, Biological; Neurodegenerative diseases; Pediatrics; Phagocytosis; Phenotype; Phenotypes; Phenotyping; Protective Agents - pharmacology; Reproducibility of Results; X-Box Binding Protein 1 - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04045-4

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.