Dysregulated Lipid Metabolism and Its Role in α-Synucleinopathy in Parkinson's Disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease, the main pathological hallmark of which is the accumulation of α-synuclein (α-syn) and the formation of filamentous aggregates called Lewy bodies in the brainstem, limbic system, and cortical areas. Lipidomics is a newly emerging field which can provide fresh insights and new answers that will enhance our capacity for early diagnosis, tracking disease progression, predicting critical endpoints, and identifying risk in pre-symptomatic persons. In recent years, lipids have been implicated in many aspects of PD pathology. Biophysical and lipidomic studies have demonstrated that α-syn binds preferentially not only to specific lipid families but also to specific molecular species and that these lipid-protein complexes enhance its interaction with synaptic membranes, influence its oligomerization and aggregation, and interfere with the catalytic activity of cytoplasmic lipid enzymes and lysosomal lipases, thereby affecting lipid metabolism. The genetic link between aberrant lipid metabolism and PD is even more direct, with mutations in GBA and SMPD1 enhancing PD risk in humans and loss of GALC function increasing α-syn aggregation and accumulation in experimental murine models. Moreover, a number of lipidomic studies have reported PD-specific lipid alterations in both patient brains and plasma, including alterations in the lipid composition of lipid rafts in the frontal cortex. A further aspect of lipid dysregulation promoting PD pathogenesis is oxidative stress and inflammation, with proinflammatory lipid mediators such as platelet activating factors (PAFs) playing key roles in arbitrating the progressive neurodegeneration seen in PD linked to α-syn intracellular trafficking. Lastly, there are a number of genetic risk factors of PD which are involved in normal lipid metabolism and function. Genes such as PLA2G6 and SCARB2, which are involved in glycerophospholipid and sphingolipid metabolism either directly or indirectly are associated with risk of PD. This review seeks to describe these facets of metabolic lipid dysregulation as they relate to PD pathology and potential pathomechanisms involved in disease progression, while highlighting incongruous findings and gaps in knowledge that necessitate further research.

Keywords: Parkinson’s disease; fatty acids; gangliosides; glucocerebrosidase (GBA); glycerophospholipids; lipids; sphingolipids; α-synuclein.

FIGURE 1

Lipid involvement in the aggregation and propagation of α-synuclein. Upon accumulation of unfolded α-syn, the monomers interact to form dimers, which can further grow to oligomers. These processes can take place both in the cytoplasm and in association with different cellular membranes. When soluble monomers continue to attach to oligomers, this eventually gives rise to amyloid fibrils, which can accumulate and form proteinaceous inclusions called Lewy bodies. α-Syn accumulation, oligomerization, and fibrillogenesis is highly affected by the lipid composition of the membranes it binds to, with a number of lipid species enhancing various steps of the process, as indicated on the diagram. The α-synuclein oligomers and fibrils formed are highly cytotoxic, leading to neurodegeneration. Cardiolipin is able to pull α-syn monomers from oligomeric fibrils, thereby buffering the toxicity. DHA, docosahexaenoic acid; GM1 and GM3, gangliosides; GPE, glycerophosphoethanolamine; GPI, glycerophosphoinositol; PUFAs, polyunsaturated fatty acids; TAGs, triacylglycerols. Figure was adapted from Lashuel et al. (2013).

FIGURE 2

Schematic representation of the role of α-synuclein in lipid uptake and metabolism. α-syn deficiency inhibits the uptake of palmitic acid and arachidonic acid and their further metabolism into glycerophosphocholine, while there is an increase in the incorporation of docosahexaenoic acid into glycerophosphoethanolamine, glycerophosphoinositol, and glycerophosphoserine. The absence of α-syn also reduces levels of phosphatidylglycerol and cardiolipin in mitochondria. Mutant α-synuclein has been shown to enhance the activity of acyl-CoA synthetase and lead to an increased generation of triacylglycerols, while wild-type α-synuclein may inhibit phospholipase D2, which hydrolyzes glycerophospholipids into diacylglycerols and phosphatidic acid. DAG, diacylglycerol; FA, fatty acid; GPC, glycerophosphocholine; GPE, glycerophosphoethanolamine; GPI, glycerophosphoinositol; GPS, glycerophosphoserine; TAG, triacylglycerol.

FIGURE 3

Overview of lipid biosynthetic and metabolic pathways indicating lipid changes which have been observed in Parkinson’s disease. Fatty acid biosynthesis begins with the conversion of acetyl-CoA to malonyl-CoA. The repeated condensation of these two fatty acyl-CoA’s results in palmitic acid, which is 16 carbons long and fully saturated. Monounsaturated fatty acids are then formed by the introduction of a double bond at carbon 9. PUFAs are generated by further desaturations and elongations. Glycerophospholipids result from the condensation of both saturated and unsaturated fatty acids with glycerol-3-phosphate. For the formation of sphingolipids, fatty acids require activation to acyl-CoA’s which then undergo condensation with serine. The attachment of various head groups like phosphocholine and hexosyl moieties gives rise to sphingomyelin and hexosyl-ceramides, respectively. Gangliosides are formed by the addition of a sialic acid to lactosyl-ceramides for GM3, as well as N-acetylgalactosamine to generate GM1 and GM2. Arachidonic acid, one of the two most enriched polyunsaturated fatty acids in the human brain, is used in the synthesis of HETE and other eicosanoids. For cholesterol synthesis, acetyl-CoA is first converted to acetoacetyl-CoA, followed by addition of another acyl group to form HMG-CoA. This is then processed into mevalonate, which through a number of subsequent reactions becomes cholesterol. Lipidomics methods employing liquid chromatography mass spectrometry have been able to reveal many lipid alterations in cells, post-mortem brain tissue and plasma from patients with PD which in the future could be developed for use as prognostic and diagnostic biomarkers. CDP-DAG, cytidine diphosphate-diacylglycerol; FA, fatty acid; HETE, hydroxyeicosatetraenoic acid; HMG-CoA, 3-methylglutaryl-3-hydroxy-CoA; GPC, glycerophosphocholine; GPE, glycerophosphoethanolamine; PG, phosphoglycerol; GPI, glycerophosphoinositol; GPS, glycerophosphoserine.