FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons

• Main Authors: Ho, Wan Yun, Chak, Li-Ling, Hor, Jin-Hui, Liu, Fujia, Diaz-Garcia, Sandra, Chang, Jer-Cherng, Sanford, Emma, Rodriguez, Maria J., Alagappan, Durgadevi, Lim, Su Min, Cho, Yik-Lam, Shimizu, Yuji, Sun, Alfred Xuyang, Tyan, Sheue-Houy, Koo, Edward, Kim, Seung Hyun, Ravits, John, Ng, Shi-Yan, Okamura, Katsutomo, Ling, Shuo-Chien
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2024
• Subjects: Medicine, Health and Life Sciences; Cellular neuroscience; Natural sciences
• Online Access: https://hdl.handle.net/10356/173808
• Institution: Nanyang Technological University

MicroRNAs (miRNAs) modulate mRNA expression, and their deregulation contributes to various diseases including amyotrophic lateral sclerosis (ALS). As fused in sarcoma (FUS) is a causal gene for ALS and regulates biogenesis of miRNAs, we systematically analyzed the miRNA repertoires in spinal cords and hippocampi from ALS-FUS mice to understand how FUS-dependent miRNA deregulation contributes to ALS. miRNA profiling identified differentially expressed miRNAs between different central nervous system (CNS) regions as well as disease states. Among the up-regulated miRNAs, miR-1197 targets the pro-survival pseudokinase Trib2. A reduced TRIB2 expression was observed in iPSC-derived motor neurons from ALS patients. Pharmacological stabilization of TRIB2 protein with a clinically approved cancer drug rescues the survival of iPSC-derived human motor neurons, including those from a sporadic ALS patient. Collectively, our data indicate that miRNA profiling can be used to probe the molecular mechanisms underlying selective vulnerability, and TRIB2 is a potential therapeutic target for ALS.