2. Academic Validation
  3. FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons

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

  • iScience. 2023 Oct 6;26(11):108152. doi: 10.1016/j.isci.2023.108152.
Wan Yun Ho 1 2,  Li-Ling Chak 1 3,  Jin-Hui Hor 4,  Fujia Liu 1,  Sandra Diaz-Garcia 5,  Jer-Cherng Chang 1,  Emma Sanford 1,  Maria J Rodriguez 5,  Durgadevi Alagappan 1,  Su Min Lim 6,  Yik-Lam Cho 1,  Yuji Shimizu 7,  Alfred Xuyang Sun 2,  Sheue-Houy Tyan 5 8,  Edward Koo 1 5 8,  Seung Hyun Kim 6,  John Ravits 5,  Shi-Yan Ng 4,  Katsutomo Okamura 3 7 9,  Shuo-Chien Ling 1 2 10
Affiliations

Affiliations

  • 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore.
  • 2 Programs in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore 169857, Singapore.
  • 3 Temasek Lifesciences Laboratory, Singapore 117604, Singapore.
  • 4 Institute of Molecular and Cellular Biology, A∗STAR Research Entities, 61 Biopolis Drive, Singapore 138673, Singapore.
  • 5 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • 6 Department of Neurology, Biomedical Research Institute, Hanyang University College of Medicine, Seoul 04763, Republic of Korea.
  • 7 Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
  • 8 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore.
  • 9 School of Biological Sciences, Nanyang Technological University, Singapore 639798, Singapore.
  • 10 Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore.
PMID: 37920668 DOI: 10.1016/j.isci.2023.108152
Abstract

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.

Keywords

Cellular neuroscience; Natural sciences; Neuroscience; Physiology; Systems neuroscience.

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