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Multiomic Analysis of ALS Pinpoints Altered Lipid Metabolism as Potential Therapeutic Target

NEW YORK – Researchers in the US, South Korea, and Germany have found that an altered step in the process of lipid metabolism could serve as a therapeutic target for amyotrophic lateral sclerosis (ALS).

In a study published on Monday in Nature Neuroscience, the researchers noted that the cause of ALS remains unclear. Specifically, they said, the basis for why spinal motor neurons (sMNs) are selectively vulnerable to degeneration while ocular motor neurons (oMNs) resist degeneration in ALS has yet to be elucidated.

In order to clarify the biological underpinnings of this dynamic, the researchers conducted a comparative multiomic analysis of human induced pluripotent stem cell-derived sMNs and oMNs to identify shared metabolic perturbations in inherited and sporadic ALS sMNs. The analysis revealed dysregulation in various lipid metabolism pathways and their related genes, especially in the arachidonic acid metabolic pathway.

Importantly, follow-up targeted metabolomics studies confirmed these findings in the sMNs of 17 ALS human induced pluripotent stem cell lines, identifying elevated levels of arachidonic acid. But the researchers also found that the oMNs of the cell lines had normal metabolic pathways.

When the researchers reduced arachidonic acid levels through pharmacological means, they found that this was sufficient to reverse ALS-related phenotypes in both human sMNs and in vivo in Drosophila and SOD1G93A mouse models.

Collectively, these findings pinpoint a catalytic step of lipid metabolism as a potential therapeutic target for ALS," the authors wrote.

Further, the investigators attempted to pinpoint specific pathways using transcriptome profiles and incorporating metabolomics analysis. They independently conducted targeted metabolomics of four ALS-derived sMN differentiation cultures to confirm the multiomic results, and were able to confirm 29 highly enriched and 22 downregulated metabolites common in four ALS hiPSC-derived sMN cultures.

Interestingly, they noted that the results of metabolomics and multiomics not only consistently showed the lipid metabolism pathways to be dysregulated, but also the pentose phosphate pathway as well as histidine metabolism and purine/pyrimidine metabolism. Aberration of the pentose phosphate pathway together with nucleotide metabolism might be a metabolic signature of higher burden of DNA damage due to higher reactive oxygen species levels and redox imbalance in ALS sMNs compared to healthy-derived sMNs or ALS-derived oMNs.

Taken together, the researchers said, these data clearly show that there is aberrant lipid homeostasis in sMN cultures of ALS hiPSCs and also further imply that dysregulated lipid metabolic pathways might serve as therapeutic target for individuals with ALS.

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