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Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme
Sarah Lépine1,2,3, Gilles Maussion1, Alexandria Schneider1
1Early Drug Discovery Unit (EDDU), The Neuro-Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, H3A 1A1, Canada.
Scientific Reports
|August 5, 2025
Summary
Investigating amyotrophic lateral sclerosis (ALS), this study reveals that TARDBP mutations alter RNA expression in motor neurons. A NEDD8-activating enzyme inhibitor, MLN4924, improved neuronal function, suggesting a therapeutic target for ALS.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no cure, linked to RNA homeostasis disruption.
- TDP-43 protein dysregulation is a key feature of ALS, with mutations in its gene (TARDBP) identified.
- Understanding the transcriptional changes caused by TARDBP mutations is crucial for developing ALS treatments.
Purpose of the Study:
- To characterize the transcriptional landscape alterations in motor neurons (MNs) due to ALS-linked TARDBP mutations.
- To identify potential therapeutic compounds that can restore normal gene expression patterns in ALS models.
Main Methods:
- Whole-transcriptome profiling of motor neurons derived from induced pluripotent stem cells (iPSCs) carrying specific TARDBP mutations (p.A382T, p.G348C).
- Utilizing mutation-induced gene expression signatures and the Connectivity Map database for compound prediction.
- In vitro testing of top-scoring compounds for their effect on cell viability and neuronal activity.
Main Results:
- TARDBP mutations significantly altered messenger RNA (mRNA) and microRNA expression profiles in the 14q32 cluster of MNs.
- Computational analysis identified compounds predicted to reverse these mutation-induced expression changes.
- The NEDD8-activating enzyme inhibitor MLN4924 demonstrated efficacy in improving MN viability and neuronal activity.
Conclusions:
- TARDBP mutations induce significant transcriptional dysregulation in motor neurons relevant to ALS.
- Targeting protein post-translational modification, specifically NEDDylation, presents a potential therapeutic strategy for TDP-43-related ALS.
- MLN4924 shows promise as a therapeutic agent for improving neuronal health in ALS models.
