FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons
Wan Yun Ho,
Li-Ling Chak,
Jin-Hui Hor,
Fujia Liu,
Sandra Diaz-Garcia,
Jer-Cherng Chang,
Emma Sanford,
Maria J. Rodriguez,
Durgadevi Alagappan,
Su Min Lim,
Yik-Lam Cho,
Yuji Shimizu,
Alfred Xuyang Sun,
Sheue-Houy Tyan,
Edward Koo,
Seung Hyun Kim,
John Ravits,
Shi-Yan Ng,
Katsutomo Okamura,
Shuo-Chien Ling
Affiliations
Wan Yun Ho
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore; Programs in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore 169857, Singapore
Li-Ling Chak
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore; Temasek Lifesciences Laboratory, Singapore 117604, Singapore
Jin-Hui Hor
Institute of Molecular and Cellular Biology, A∗STAR Research Entities, 61 Biopolis Drive, Singapore 138673, Singapore
Fujia Liu
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore
Sandra Diaz-Garcia
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
Jer-Cherng Chang
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore
Emma Sanford
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore
Maria J. Rodriguez
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
Durgadevi Alagappan
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore
Su Min Lim
Department of Neurology, Biomedical Research Institute, Hanyang University College of Medicine, Seoul 04763, Republic of Korea
Yik-Lam Cho
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore
Yuji Shimizu
Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
Alfred Xuyang Sun
Programs in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore 169857, Singapore
Sheue-Houy Tyan
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore
Edward Koo
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore
Seung Hyun Kim
Department of Neurology, Biomedical Research Institute, Hanyang University College of Medicine, Seoul 04763, Republic of Korea
John Ravits
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
Shi-Yan Ng
Institute of Molecular and Cellular Biology, A∗STAR Research Entities, 61 Biopolis Drive, Singapore 138673, Singapore
Katsutomo Okamura
Temasek Lifesciences Laboratory, Singapore 117604, Singapore; Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan; School of Biological Sciences, Nanyang Technological University, Singapore 639798, Singapore; Corresponding author
Shuo-Chien Ling
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore; Programs in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore 169857, Singapore; Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore; Corresponding author
Summary: 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.
