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

doi:10.1016/j.isci.2023.108152

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. eCollection 2023 Nov 17.

Authors

Wan Yun Ho^{1

2}, Li-Ling Chak^{1

3}, Jin-Hui Hor⁴, Fujia Liu¹, Sandra Diaz-Garcia⁵, Jer-Cherng Chang¹, Emma Sanford¹, Maria J Rodriguez⁵, Durgadevi Alagappan¹, Su Min Lim⁶, Yik-Lam Cho¹, Yuji Shimizu⁷, Alfred Xuyang Sun², Sheue-Houy Tyan^{5

8}, Edward Koo^{1

5

8}, Seung Hyun Kim⁶, John Ravits⁵, Shi-Yan Ng⁴, Katsutomo Okamura^{3

7

9}, Shuo-Chien Ling^{1

2

10}

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.

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.