Decanoic acid extends lifespan and modulates metabolism in models of PLA2G6-associated neurodegeneration.

PLA2G6-associated neurodegeneration (PLAN) is a group of rare genetic disorders characterised by progressive neurodegeneration resulting from mutations in the PLA2G6 gene, encoding a calcium-independent phospholipase enzyme. Here, we have explored the effects of decanoic acid (DA), a medium-chain fatty acid, in the fruit fly Drosophila melanogaster models of PLAN and show that DA treatment significantly extends the lifespan, reduces bang sensitivity and improves resistance to heat shock stress. Transcriptional analysis showed that DA affects genes in key signalling pathways, including Insulin/Insulin-like Growth Factor, mTOR, heat shock response, Sirtuin, autophagy and mitochondrial function. Additionally, DA treatment alters the metabolite profiles in PLAN model flies, with the most pronounced changes observed in gut tissue. Pathway analysis of these metabolomic shifts highlights potential therapeutic effects of DA in several pathways, including ATP-binding cassette (ABC) transporters, purine metabolism, cAMP signalling and neuroactive ligand-receptor interactions. These findings suggest that DA may be a promising therapeutic agent for PLAN, offering insights into the mechanisms of the disease and paving the way for future research on medium-chain fatty acids as potential treatments for neurodegenerative diseases.