Condensate-Driven Triglyceride Depletion Links α-Synuclein to Mitochondrial Dysfunction

Zhang, T., Goya, M. E., Herron-Bedoya, A., van der Weerd, J. C., Tsagkari, D., Couzijn, S., Gürgöndü, L., Seinstra, R. I., Fokkema, M. R. H., Chang, M., Tavernarakis, N., Kuipers, F., Nollen, E.

University of GroningenUniversity of Groningen · biorxiv

Paper

Abstract

Inclusions of -Synuclein (Syn) characterize multiple age-related neurodegenerative diseases, including Parkinson's disease (PD) and Multiple System Atrophy (MSA). While interactions between Syn and lipids are known to contribute to Syn pathobiology, the precise cellular mechanisms that link lipids to Syn toxicity have yet to be elucidated. Through lipidomic profiling of Caenorhabditis elegans, we found that Syn progressively alters lipid metabolism in aging worms. Syn strongly reduces overall content of triacylglycerols (TAG) and disrupts the structure of lipid droplets (LD). These pathological changes depend on Syn's properties to condensate and form inclusions. Apart from lowering TAG levels, Syn also increases the proportion of long-chain unsaturated fatty acids (LCUFAs). Consequently, genetic inhibition of LCUFA biosynthesis alleviates Syn-induced loss of C. elegans motility. Strikingly, bypassing lipid metabolic defects by supplementing Medium Chain Fatty Acids (MCFAs) restores the Syn-impaired mitochondrial response and rescues motility. These results link Syn condensation to impaired TAG metabolism, which reduces mitochondrial function and enhances overall toxicity. Together with the finding that plasma TAGs are lowered in Parkinson patient cohorts, these results suggest that restoring TAG metabolism could alleviate Syn-induced toxicity in Parkinson's and other age-related synucleinopathies.

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Research summary

The paper claims that α-Synuclein condensation leads to impaired triglyceride metabolism, which in turn affects mitochondrial function and contributes to toxicity in age-related neurodegenerative diseases. This research is relevant as it explores the underlying mechanisms linking lipid metabolism and mitochondrial dysfunction in the context of aging and neurodegeneration, potentially addressing root causes of age-related diseases.

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