Journal Article

Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924

Lépine, Sarah, Dilliott, Allison A., Castellanos-Montiel, María José, Chaineau, Mathilde, Spiegelman, Dan, Franco-Flores, Anna Krystina, Nauleau-Javaudin, Angela, Durcan, Thomas M., Ambriz, Georgina Jiménez, Haghi, Ghazal, Maussion, Gilles, Schneider, Alexandria, Farhan, Sali M. K., Abdian, Narges, Fiorini, Michael R., Gursu, Lale

2025

Overview

A growing body of knowledge implicates perturbed RNA homeostasis in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that currently has no cure and few available treatments. Dysregulation of the multifunctional RNA-binding protein TDP-43 is increasingly regarded as a convergent feature of this disease, evidenced at the neuropathological level by the detection of TDP-43 pathology in most patient tissues, and at the genetic level by the identification of disease-associated mutations in its coding gene TARDBP . To characterize the transcriptional landscape induced by TARDBP mutations, we performed whole-transcriptome profiling of motor neurons (MNs) differentiated from two knock-in iPSC lines expressing the ALS-linked TDP-43 variants p.A382T or p.G348C. Our results show that the TARDBP mutations significantly altered the expression profiles of mRNAs and microRNAs of the 14q32 cluster in MNs. Using mutation-induced gene signatures and the Connectivity Map database, we identified compounds predicted to restore gene expression toward wild-type levels. Among top-scoring compounds selected for further investigation, the NEDD8-activating enzyme inhibitor MLN4924 effectively improved cell viability and neuronal activity, highlighting a possible role for protein post-translational modification via NEDDylation in the pathobiology of TDP-43 in ALS.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 692/308/1426 / 692/617/375/1917 / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Cell adhesion & migration / Cell viability / Cyclopentanes - pharmacology / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Enzyme inhibitors / Enzymes / Gene expression / Gene Expression Profiling / Gene Knock-In Techniques / Homeostasis / Humanities and Social Sciences / Humans / Induced Pluripotent Stem Cells - metabolism / Metabolism / MicroRNAs / miRNA / Motor neurons / Motor Neurons - drug effects / Motor Neurons - metabolism / multidisciplinary / Mutation / NEDD8 Protein - antagonists & inhibitors / NEDD8 Protein - metabolism / Neural networks / Neurodegenerative diseases / Ontology / Post-translation / Proteins / Pyrimidines - pharmacology / RNA-binding protein / Science / Science (multidisciplinary) / Spinal cord / Stem cells / Transcriptome / Transcriptomes