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The role of α-synuclein in brain lipid metabolism: a downstream impact on brain inflammatory response

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Abstract

α-Synuclein (Snca) is an abundant small cytosolic protein (140 amino acids) that is expressed in the brain, although its physiological role is poorly defined. Consistent with its ubiquitous distribution in the brain, we and others have established a role for Snca in brain lipid metabolism and downstream events such as neuroinflammation. In astrocytes, Snca is important for fatty acid uptake and trafficking, where its deletion decreases 16:0 and 20:4n-6 uptake and alters targeting to specific lipid pools. Although Snca has no impact on 22:6n-3 uptake into astrocytes, it is important for its targeting to lipid pools. Similar results for fatty acid uptake from the plasma are seen in studies using whole mice coupled with steady-state kinetic modeling. We demonstrate in gene-ablated mice a significant reduction in the incorporation rate of 20:4n-6 into brain phospholipid pools due to reduced recycling of 20:4n-6 through the ER-localized long-chain acyl-CoA synthetases (Acsl). This reduction results in a compensatory increase in the incorporation rate of 22:6n-3 into brain phospholipids. Snca is also important for brain and astrocyte cholesterol metabolism, where its deletion results in an elevation of cholesterol and cholesteryl esters. This increase may be due to the interaction of Snca with membrane-bound enzymes involved in lipid metabolism such as Acsl. Snca is critical in modulating brain prostanoid formation and microglial activities. In the absence of Snca, microglia are basally activated and demonstrate increased proinflammatory cytokine secretion. Thus, Snca, through its modulation of brain lipid metabolism, has a critical role in brain inflammatory responses.

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Acknowledgments

We thank Dr. Robert Nussbaum for providing the mice used in this collective work and look forward to our continued collaboration. We thank Dr. Carole Haselton and Angie Floden for their excellent technical work. This work was supported by a project to EJM and CKC on an NIH COBRE grant P20 RR17699 and by an NIH grant R21 NS043697 to EJM.

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  1. Gwendolyn Barceló-Coblijn

    Present address: Department of Biology, University of the Balearic Islands, Palma, Spain

  2. Paula I. Castagnet

    Present address: Department of Biology, Ave Maria University, 5050 Ave Maria Blvd, Ave Maria, FL, USA

Authors and Affiliations

  1. Department of Pharmacology, Physiology, and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, 501 N. Columbia Rd., Grand Forks, ND, 58202-9037, USA

    Mikhail Y. Golovko, Gwendolyn Barceló-Coblijn, Paula I. Castagnet, Susan Austin, Colin K. Combs & Eric J. Murphy

  2. Department of Chemistry, University of North Dakota, Grand Forks, ND, 58202-9037, USA

    Eric J. Murphy

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  1. Mikhail Y. Golovko
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Correspondence to Eric J. Murphy.

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Golovko, M.Y., Barceló-Coblijn, G., Castagnet, P.I. et al. The role of α-synuclein in brain lipid metabolism: a downstream impact on brain inflammatory response. Mol Cell Biochem 326, 55–66 (2009). https://doi.org/10.1007/s11010-008-0008-y

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