Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress

• Published in: Cell reports (Cambridge) Vol. 36; no. 10; p. 109685
• Main Authors: Markmiller, Sebastian, Sathe, Shashank, Server, Kari L., Nguyen, Thai B., Fulzele, Amit, Cody, Neal, Javaherian, Ashkan, Broski, Sara, Finkbeiner, Steven, Bennett, Eric J., Lécuyer, Eric, Yeo, Gene W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.09.2021
• Subjects: amyotrophic lateral sclerosis (ALS); Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Cell Death - genetics; Cell Death - physiology; cellular stress response; Cytoplasmic Granules - metabolism; Cytoplasmic Ribonucleoprotein Granules - metabolism; Cytoplasmic Ribonucleoprotein Granules - pathology; DNA-Binding Proteins - metabolism; hnRNPA2B1; Humans; motor neurons; Motor Neurons - metabolism; Mutation - genetics; neurodegeneration; nucleocytoplasmic transport; protein aggregation; RNA localization; RNA, Messenger - metabolism; RNA-Binding Proteins - metabolism; stress granules; TDP-43; motor neurons; hnRNPA2B1; TDP-43; protein aggregation; stress granules; neurodegeneration; nucleocytoplasmic transport; RNA localization; cellular stress response; amyotrophic lateral sclerosis (ALS)
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109685

Persistent cytoplasmic aggregates containing RNA binding proteins (RBPs) are central to the pathogenesis of late-onset neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). These aggregates share components, molecular mechanisms, and cellular protein quality control pathways with stress-induced RNA granules (SGs). Here, we assess the impact of stress on the global mRNA localization landscape of human pluripotent stem cell-derived motor neurons (PSC-MNs) using subcellular fractionation with RNA sequencing and proteomics. Transient stress disrupts subcellular RNA and protein distributions, alters the RNA binding profile of SG- and ALS-relevant RBPs and recapitulates disease-associated molecular changes such as aberrant splicing of STMN2. Although neurotypical PSC-MNs re-establish a normal subcellular localization landscape upon recovery from stress, cells harboring ALS-linked mutations are intransigent and display a delayed-onset increase in neuronal cell death. Our results highlight subcellular molecular distributions as predictive features and underscore the utility of cellular stress as a paradigm to study ALS-relevant mechanisms. [Display omitted] •CeFra-seq applied to a range of cell types reveals basic rules of RNA localization•Transient stress disrupts subcellular mRNA and protein localization landscapes•Stress alters RNA binding of RBPs, including TDP-43, and alters splicing of STMN2•Stress induces persistent RNA localization changes and cell death in ALS neurons Markmiller et al. show that transient stress disrupts subcellular RNA and protein distributions in stem cell-derived motor neurons, recapitulating ALS-associated changes. Neurotypical motor neurons recover subcellular patterns after stress. However, motor neurons harboring ALS-linked mutations exhibit persistent RNA localization changes and eventual cell death.