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Integrated Omic Analysis Delineates Pathways Modulating Toxic TDP-43 Protein Aggregates in Amyotrophic Lateral
Saiswaroop Rajaratnam1, Akhil P Soman1,2, Kanikaram Sai Phalguna1
1Disease Biology Lab, Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Prasanthi Nilayam, Anantapur 515134, Andhra Pradesh, India.
Cells
|May 13, 2023
Summary
This study reveals metabolic pathway disruptions in amyotrophic lateral sclerosis (ALS), a motor neuron disease. Findings suggest potential dietary and supplemental interventions for managing ALS progression.
Area of Science:
- Neuroscience
- Metabolomics
- Genomics
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal, incurable neurodegenerative disease impacting motor neurons.
- Familial ALS is often linked to specific gene mutations, including TDP-43.
- Multi-omics approaches in patient and model systems are crucial for understanding ALS pathogenesis.
Purpose of the Study:
- To investigate deregulated signaling and metabolic pathways in ALS using an integrated transcriptomic and metabolomic analysis.
- To identify key metabolic alterations associated with TDP-43 protein expression, a common factor in ALS.
Main Methods:
- Integrated transcriptomic and metabolomic analysis of a TDP-43 expressing yeast model.
- Analysis of GEO datasets from mouse models and ALS patient motor neurons.
- Validation experiments in yeast using metabolite addition and gene knock-out.
Main Results:
- Identified deregulation in the TCA cycle, single carbon metabolism, glutathione metabolism, and fatty acid metabolism.
- Transcriptomic data from mouse models and ALS patients showed significant overlap with yeast model findings.
- Validated key metabolic pathway alterations in the yeast model.
Conclusions:
- The study highlights the potential roles of the TCA cycle, cellular redox, NAD metabolism, and fatty acid metabolism in ALS.
- Suggests that supplementation with reduced glutathione, nicotinate, and adherence to a ketogenic diet may offer therapeutic benefits for ALS management.
