Abstract
On the basis of extensive mechanistic research over three decades, Parkinson disease (PD) and related synucleinopathies have been proposed to be combined proteinopathies and lipidopathies. Evidence strongly supports a physiological and pathogenic interplay between the disease-associated protein α-synuclein and lipids, with a demonstrable role for lipids in modulating PD phenotypes in the brain. Here, we refine this hypothesis by proposing PD to be a disease specifically involving metabolic dysregulation of fatty acids, a ‘fatty acidopathy’. We review extensive findings from many laboratories supporting the perspective that PD centres on fatty acid dyshomeostasis — alterations in the fatty acid-ome — as the critical feature of lipid aberration in PD and other α-synucleinopathies. This construct places transient α-synuclein binding to fatty acid side chains of cytoplasmic vesicles as a principal contributor to the biology of PD-relevant α-synuclein–membrane interactions. We propose that α-synuclein–fatty acid interactions in the fatty acid-rich brain are interdependent determinants of the gradual progression from neuronal health to PD, with attendant therapeutic implications.
Key points
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Parkinson disease (PD) and related α-synucleinopathies have increasingly been considered lipidopathies as well as proteinopathies.
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Extensive evidence reviewed herein supports both physiological and pathogenic interplay between α-synuclein and fatty acids as determinants of progression from neuronal health to PD.
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α-Synuclein homeostasis is affected by membrane fatty acid composition, and dysregulated fatty acid metabolism alters transient α-synuclein membrane binding, including at synaptic vesicles.
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We propose that PD is a fatty acidopathy, with fatty acid side chain dyshomeostasis being a chief contributor to lipid aberrations in synucleinopathies.
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The fatty acid-ome holds promise for identifying and validating PD biomarkers and therapeutic targets.
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References
Fanning, S., Selkoe, D. & Dettmer, U. Parkinson’s disease: proteinopathy or lipidopathy? npj Parkinsons Dis. 6, 3 (2020).
Fanning, S., Selkoe, D. & Dettmer, U. Vesicle trafficking and lipid metabolism in synucleinopathy. Acta Neuropathol. https://doi.org/10.1007/s00401-020-02177-z (2020).
Flores-Leon, M. & Outeiro, T. F. More than meets the eye in Parkinson’s disease and other synucleinopathies: from proteinopathy to lipidopathy. Acta Neuropathol. 146, 369–385 (2023).
Klemann, C. et al. Integrated molecular landscape of Parkinson’s disease. npj Parkinsons Dis. 3, 14 (2017).
Shahmoradian, S. H. et al. Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nat. Neurosci. 22, 1099–1109 (2019).
Moors, T. E. et al. The subcellular arrangement of α-synuclein proteoforms in the Parkinson’s disease brain as revealed by multicolor STED microscopy. Acta Neuropathol. https://doi.org/10.1007/s00401-021-02329-9 (2021).
Roy, S. & Wolman, L. Ultrastructural observations in Parkinsonism. J. Pathol. 99, 39–44 (1969).
Forno, L. S. & Norville, R. L. Ultrastructure of Lewy bodies in the stellate ganglion. Acta Neuropathol. 34, 183–197 (1976).
Dickson, D. W. et al. Diffuse Lewy body disease: light and electron microscopic immunocytochemistry of senile plaques. Acta Neuropathol. 78, 572–584 (1989).
Moors, T. E. & Milovanovic, D. Defining a Lewy body: running up the hill of shifting definitions and evolving concepts. J. Parkinsons Dis. 14, 17–33 (2024).
Bodner, C. R., Dobson, C. M. & Bax, A. Multiple tight phospholipid-binding modes of α-synuclein revealed by solution NMR spectroscopy. J. Mol. Biol. 390, 775–790 (2009).
Bodner, C. R., Maltsev, A. S., Dobson, C. M. & Bax, A. Differential phospholipid binding of α-synuclein variants implicated in Parkinson’s disease revealed by solution NMR spectroscopy. Biochemistry 49, 862–871 (2010).
Ruiperez, V., Darios, F. & Davletov, B. Alpha-synuclein, lipids and Parkinson’s disease. Prog. Lipid Res. 49, 420–428 (2010).
Stockl, M., Fischer, P., Wanker, E. & Herrmann, A. α-Synuclein selectively binds to anionic phospholipids embedded in liquid-disordered domains. J. Mol. Biol. 375, 1394–1404 (2008).
Westphal, C. H. & Chandra, S. S. Monomeric synucleins generate membrane curvature. J. Biol. Chem. 288, 1829–1840 (2013).
Runwal, G. & Edwards, R. H. The membrane interactions of synuclein: physiology and pathology. Annu. Rev. Pathol. 16, 465–485 (2021).
Davidson, W. S., Jonas, A., Clayton, D. F. & George, J. M. Stabilization of α-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 273, 9443–9449 (1998).
Fanning, S. et al. Lipidomic analysis of α-synuclein neurotoxicity identifies stearoyl CoA desaturase as a target for Parkinson treatment. Mol. Cell 73, 1001–1014.e8 (2018).
Golovko, M. Y. et al. α-synuclein gene deletion decreases brain palmitate uptake and alters the palmitate metabolism in the absence of α-synuclein palmitate binding. Biochemistry 44, 8251–8259 (2005).
Golovko, M. Y., Rosenberger, T. A., Feddersen, S., Faergeman, N. J. & Murphy, E. J. α-Synuclein gene ablation increases docosahexaenoic acid incorporation and turnover in brain phospholipids. J. Neurochem. 101, 201–211 (2007).
Rappley, I. et al. Lipidomic profiling in mouse brain reveals differences between ages and genders, with smaller changes associated with α-synuclein genotype. J. Neurochem. 111, 15–25 (2009).
Golovko, M. Y. et al. Acyl-CoA synthetase activity links wild-type but not mutant α-synuclein to brain arachidonate metabolism. Biochemistry 45, 6956–6966 (2006).
Barcelo-Coblijn, G., Golovko, M. Y., Weinhofer, I., Berger, J. & Murphy, E. J. Brain neutral lipids mass is increased in α-synuclein gene-ablated mice. J. Neurochem. 101, 132–141 (2007).
Jove, M., Pradas, I., Dominguez-Gonzalez, M., Ferrer, I. & Pamplona, R. Lipids and lipoxidation in human brain aging. Mitochondrial ATP-synthase as a key lipoxidation target. Redox Biol. 23, 101082 (2019).
O’Brien, J. S. & Sampson, E. L. Fatty acid and fatty aldehyde composition of the major brain lipids in normal human gray matter, white matter, and myelin. J. Lipid Res. 6, 545–551 (1965).
O’Brien, J. S. & Sampson, E. L. Lipid composition of the normal human brain: gray matter, white matter, and myelin. J. Lipid Res. 6, 537–544 (1965).
Di Pardo, A. & Maglione, V. The S1P axis: new exciting route for treating Huntington’s disease. Trends Pharmacol. Sci. 39, 468–480 (2018).
Block, R. C., Dorsey, E. R., Beck, C. A., Brenna, J. T. & Shoulson, I. Altered cholesterol and fatty acid metabolism in Huntington disease. J. Clin. Lipidol. 4, 17–23 (2010).
Foley, P. Lipids in Alzheimer’s disease: a century-old story. Biochim. Biophys. Acta 1801, 750–753 (2010).
Morgado, I. & Garvey, M. Lipids in amyloid-β processing, aggregation, and toxicity. Adv. Exp. Med. Biol. 855, 67–94 (2015).
van Wijk, N. et al. Nutrients required for phospholipid synthesis are lower in blood and cerebrospinal fluid in mild cognitive impairment and Alzheimer’s disease dementia. Alzheimers Dement. (Amst.) 8, 139–146 (2017).
Trimbuch, T. et al. Synaptic PRG-1 modulates excitatory transmission via lipid phosphate-mediated signaling. Cell 138, 1222–1235 (2009).
Etschmaier, K. et al. Adipose triglyceride lipase affects triacylglycerol metabolism at brain barriers. J. Neurochem. 119, 1016–1028 (2011).
Sastry, P. S. Lipids of nervous tissue: composition and metabolism. Prog. Lipid Res. 24, 69–176 (1985).
Burre, J. The synaptic function of α-synuclein. J. Parkinsons Dis. 5, 699–713 (2015).
Bussell, R. Jr & Eliezer, D. A structural and functional role for 11-mer repeats in alpha-synuclein and other exchangeable lipid binding proteins. J. Mol. Biol. 329, 763–778 (2003).
Clayton, D. F. & George, J. M. Synucleins in synaptic plasticity and neurodegenerative disorders. J. Neurosci. Res. 58, 120–129 (1999).
Lorenzen, N., Lemminger, L., Pedersen, J. N., Nielsen, S. B. & Otzen, D. E. The N-terminus of alpha-synuclein is essential for both monomeric and oligomeric interactions with membranes. FEBS Lett. 588, 497–502 (2014).
Blauwendraat, C. et al. Insufficient evidence for pathogenicity of SNCA His50Gln (H50Q) in Parkinson’s disease. Neurobiol. Aging 64, 159 e155–159.e8 (2018).
Kruger, R. et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat. Genet. 18, 106–108 (1998).
Lesage, S. et al. G51D alpha-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann. Neurol. 73, 459–471 (2013).
Polymeropoulos, M. H. et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047 (1997).
Proukakis, C. et al. A novel alpha-synuclein missense mutation in Parkinson disease. Neurology 80, 1062–1064 (2013).
Zarranz, J. J. et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55, 164–173 (2004).
Appel-Cresswell, S. et al. Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson’s disease. Mov. Disord. 28, 811–813 (2013).
Assayag, K., Yakunin, E., Loeb, V., Selkoe, D. J. & Sharon, R. Polyunsaturated fatty acids induce alpha-synuclein-related pathogenic changes in neuronal cells. Am. J. Pathol. 171, 2000–2011 (2007).
Kiechle, M., Grozdanov, V. & Danzer, K. M. The role of lipids in the initiation of alpha-synuclein misfolding. Front. Cell Dev. Biol. 8, 562241 (2020).
Galvagnion, C. The role of lipids interacting with alpha-synuclein in the pathogenesis of Parkinson’s disease. J. Parkinsons Dis. 7, 433–450 (2017).
Fecchio, C. et al. alpha-Synuclein oligomers induced by docosahexaenoic acid affect membrane integrity. PLoS ONE 8, e82732 (2013).
Lokappa, S. B. et al. Sequence and membrane determinants of the random coil–helix transition of alpha-synuclein. J. Mol. Biol. 426, 2130–2144 (2014).
Man, W. K. et al. The docking of synaptic vesicles on the presynaptic membrane induced by alpha-synuclein is modulated by lipid composition. Nat. Commun. 12, 927 (2021).
Kubo, S. et al. A combinatorial code for the interaction of alpha-synuclein with membranes. J. Biol. Chem. 280, 31664–31672 (2005).
Beyer, K. Mechanistic aspects of Parkinson’s disease: alpha-synuclein and the biomembrane. Cell Biochem. Biophys. 47, 285–299 (2007).
O’Leary, E. I. & Lee, J. C. Interplay between alpha-synuclein amyloid formation and membrane structure. Biochim. Biophys. Acta Proteins Proteom. 1867, 483–491 (2019).
Alza, N. P., Iglesias Gonzalez, P. A., Conde, M. A., Uranga, R. M. & Salvador, G. A. Lipids at the crossroad of alpha-synuclein function and dysfunction: biological and pathological implications. Front. Cell Neurosci. 13, 175 (2019).
Sharon, R. et al. The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson’s disease. Neuron 37, 583–595 (2003).
Sharon, R. et al. alpha-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins. Proc. Natl Acad. Sci. USA 98, 9110–9115 (2001).
Lucke, C., Gantz, D. L., Klimtchuk, E. & Hamilton, J. A. Interactions between fatty acids and alpha-synuclein. J. Lipid Res. 47, 1714–1724 (2006).
Karube, H. et al. N-terminal region of alpha-synuclein is essential for the fatty acid-induced oligomerization of the molecules. FEBS Lett. 582, 3693–3700 (2008).
Wang, G. F., Li, C. & Pielak, G. J. 19F NMR studies of alpha-synuclein–membrane interactions. Protein Sci. 19, 1686–1691 (2010).
Ali, A., Holman, A. P., Rodriguez, A., Osborne, L. & Kurouski, D. Elucidating the mechanisms of alpha-synuclein–lipid interactions using site-directed mutagenesis. Neurobiol. Dis. 198, 106553 (2024).
Ali, A., Zhaliazka, K., Dou, T., Holman, A. P. & Kurouski, D. The toxicities of A30P and A53T alpha-synuclein fibrils can be uniquely altered by the length and saturation of fatty acids in phosphatidylserine. J. Biol. Chem. 299, 105383 (2023).
Perrin, R. J., Woods, W. S., Clayton, D. F. & George, J. M. Interaction of human α-synuclein and Parkinson’s disease variants with phospholipids. Structural analysis using site-directed mutagenesis. J. Biol. Chem. 275, 34393–34398 (2000).
Rhoades, E., Ramlall, T. F., Webb, W. W. & Eliezer, D. Quantification of α-synuclein binding to lipid vesicles using fluorescence correlation spectroscopy. Biophys. J. 90, 4692–4700 (2006).
Jo, E., McLaurin, J., Yip, C. M., St George-Hyslop, P. & Fraser, P. E. α-Synuclein membrane interactions and lipid specificity. J. Biol. Chem. 275, 34328–34334 (2000).
Brummel, B. E., Braun, A. R. & Sachs, J. N. Polyunsaturated chains in asymmetric lipids disorder raft mixtures and preferentially associate with α-synuclein. Biochim. Biophys. Acta Biomembr. 1859, 529–536 (2017).
Harayama, T. & Shimizu, T. Roles of polyunsaturated fatty acids, from mediators to membranes. J. Lipid Res. 61, 1150–1160 (2020).
Perrin, R. J., Woods, W. S., Clayton, D. F. & George, J. M. Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J. Biol. Chem. 276, 41958–41962 (2001).
Broersen, K., van den Brink, D., Fraser, G., Goedert, M. & Davletov, B. α-Synuclein adopts an α-helical conformation in the presence of polyunsaturated fatty acids to hinder micelle formation. Biochemistry 45, 15610–15616 (2006).
Burre, J., Sharma, M. & Sudhof, T. C. α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc. Natl Acad. Sci. USA 111, E4274–E4283 (2014).
Manna, M. & Murarka, R. K. Polyunsaturated fatty acid modulates membrane-bound monomeric α-synuclein by modulating membrane microenvironment through preferential interactions. ACS Chem. Neurosci. 12, 675–688 (2021).
Tyoe, O., Aryal, C. & Diao, J. Docosahexaenoic acid promotes vesicle clustering mediated by α-synuclein via electrostatic interaction. Eur. Phys. J. E Soft Matter 46, 96 (2023).
Bothun, G. D., Boltz, L., Kurniawan, Y. & Scholz, C. Cooperative effects of fatty acids and n-butanol on lipid membrane phase behavior. Colloids Surf. B Biointerfaces 139, 62–67 (2016).
Maulucci, G. et al. Fatty acid-related modulations of membrane fluidity in cells: detection and implications. Free Radic. Res. 50, S40–S50 (2016).
Fredriksen, K. et al. Pathological α-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of α-syn in vivo. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2108489118 (2021).
Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997).
Fujiwara, H. et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160–164 (2002).
Chia, R. et al. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat. Genet. 53, 294–303 (2021).
Mizuta, I. et al. Multiple candidate gene analysis identifies α-synuclein as a susceptibility gene for sporadic Parkinson’s disease. Hum. Mol. Genet. 15, 1151–1158 (2006).
Satake, W. et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat. Genet. 41, 1303–1307 (2009).
Simon-Sanchez, J. et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat. Genet. 41, 1308–1312 (2009).
Nalls, M. A. et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat. Genet. 46, 989–993 (2014).
Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18, 1091–1102 (2019).
Singleton, A. B. et al. α-Synuclein locus triplication causes Parkinson’s disease. Science 302, 841 (2003).
Edwards, T. L. et al. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann. Hum. Genet. 74, 97–109 (2010).
Chang, D. et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat. Genet. 49, 1511–1516 (2017).
Nuber, S. et al. A brain-penetrant stearoyl-CoA desaturase inhibitor reverses α-synuclein toxicity. Neurotherapeutics 19, 1018–1036 (2022).
Nuber, S. et al. A stearoyl-coenzyme A desaturase inhibitor prevents multiple Parkinson disease phenotypes in α-synuclein mice. Ann. Neurol. 89, 74–90 (2021).
Vincent, B. M. et al. Inhibiting stearoyl-CoA desaturase ameliorates α-synuclein cytotoxicity. Cell Rep. 25, 2742–2754.e31 (2018).
Raja, W. K. et al. Patient-derived three-dimensional cortical neurospheres to model Parkinson’s disease. PLoS ONE 17, e0277532 (2022).
Fanning, S. et al. Lipase regulation of cellular fatty acid homeostasis as a Parkinson’s disease therapeutic strategy. npj Parkinsons Dis. 8, 74 (2022).
Imberdis, T. et al. Cell models of lipid-rich α-synuclein aggregation validate known modifiers of α-synuclein biology and identify stearoyl-CoA desaturase. Proc. Natl Acad. Sci. USA 116, 20760–20769 (2019).
Nicholatos, J. W. et al. SCD inhibition protects from α-synuclein-induced neurotoxicity but is toxic to early neuron cultures. eNeuro https://doi.org/10.1523/ENEURO.0166-21.2021 (2021).
Tripathi, A. et al. Pathogenic mechanisms of cytosolic and membrane-enriched α-synuclein converge on fatty acid homeostasis. J. Neurosci. 42, 2116–2130 (2022).
Castagnet, P. I., Golovko, M. Y., Barcelo-Coblijn, G. C., Nussbaum, R. L. & Murphy, E. J. Fatty acid incorporation is decreased in astrocytes cultured from α-synuclein gene-ablated mice. J. Neurochem. 94, 839–849 (2005).
Golovko, M. Y. 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).
Kawahata, I. & Fukunaga, K. Pathogenic impact of fatty acid-binding proteins in Parkinson’s disease-potential biomarkers and therapeutic targets. Int. J. Mol. Sci. https://doi.org/10.3390/ijms242317037 (2023).
Mollenhauer, B. et al. Serum heart-type fatty acid-binding protein and cerebrospinal fluid tau: marker candidates for dementia with Lewy bodies. Neurodegener. Dis. 4, 366–375 (2007).
Kawahata, I., Sekimori, T., Oizumi, H., Takeda, A. & Fukunaga, K. Using fatty acid-binding proteins as potential biomarkers to discriminate between Parkinson’s disease and dementia with Lewy bodies: exploration of a novel technique. Int. J. Mol. Sci. https://doi.org/10.3390/ijms241713267 (2023).
Wada-Isoe, K., Imamura, K., Kitamaya, M., Kowa, H. & Nakashima, K. Serum heart-fatty acid binding protein levels in patients with Lewy body disease. J. Neurol. Sci. 266, 20–24 (2008).
Teunissen, C. E. et al. Brain-specific fatty acid-binding protein is elevated in serum of patients with dementia-related diseases. Eur. J. Neurol. 18, 865–871 (2011).
Backstrom, D. C. et al. Cerebrospinal fluid patterns and the risk of future dementia in early, incident Parkinson disease. JAMA Neurol. 72, 1175–1182 (2015).
Basso, M. et al. Proteome analysis of human substantia nigra in Parkinson’s disease. Proteomics 4, 3943–3952 (2004).
Fukui, N. et al. An α-synuclein decoy peptide prevents cytotoxic α-synuclein aggregation caused by fatty acid binding protein 3. J. Biol. Chem. 296, 100663 (2021).
Shioda, N. et al. FABP3 protein promotes α-synuclein oligomerization associated with 1-methyl-1,2,3,6-tetrahydropiridine-induced neurotoxicity. J. Biol. Chem. 289, 18957–18965 (2014).
Yabuki, Y. et al. Fatty acid binding protein 3 enhances the spreading and toxicity of α-synuclein in mouse brain. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21062230 (2020).
Oizumi, H. et al. Fatty acid-binding protein 3 expression in the brain and skin in human synucleinopathies. Front. Aging Neurosci. 13, 648982 (2021).
Cheng, A. et al. Fatty acid-binding protein 7 triggers α-synuclein oligomerization in glial cells and oligodendrocytes associated with oxidative stress. Acta Pharmacol. Sin. 43, 552–562 (2022).
Cheng, A., Jia, W., Kawahata, I. & Fukunaga, K. Impact of fatty acid-binding proteins in α-synuclein-induced mitochondrial injury in synucleinopathy. Biomedicines https://doi.org/10.3390/biomedicines9050560 (2021).
Matsuo, K. et al. Inhibition of MPTP-induced α-synuclein oligomerization by fatty acid-binding protein 3 ligand in MPTP-treated mice. Neuropharmacology 150, 164–174 (2019).
Bartels, T., Choi, J. G. & Selkoe, D. J. α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477, 107–110 (2011).
Middleton, E. R. & Rhoades, E. Effects of curvature and composition on α-synuclein binding to lipid vesicles. Biophys. J. 99, 2279–2288 (2010).
Dettmer, U., Newman, A. J., von Saucken, V. E., Bartels, T. & Selkoe, D. KTKEGV repeat motifs are key mediators of normal α-synuclein tetramerization: their mutation causes excess monomers and neurotoxicity. Proc. Natl Acad. Sci. USA 112, 9596–9601 (2015).
Dettmer, U. et al. Loss of native α-synuclein multimerization by strategically mutating its amphipathic helix causes abnormal vesicle interactions in neuronal cells. Hum. Mol. Genet. 26, 3466–3481 (2017).
Dettmer, U. et al. Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat. Commun. 6, 7314 (2015).
Dettmer, U., Newman, A. J., Luth, E. S., Bartels, T. & Selkoe, D. In vivo cross-linking reveals principally oligomeric forms of α-synuclein and β-synuclein in neurons and non-neural cells. J. Biol. Chem. 288, 6371–6385 (2013).
Wang, W. et al. A soluble α-synuclein construct forms a dynamic tetramer. Proc. Natl Acad. Sci. USA 108, 17797–17802 (2011).
Nuber, S. et al. Abrogating native α-synuclein tetramers in mice causes a L-DOPA-responsive motor syndrome closely resembling Parkinson’s disease. Neuron 100, 75–90.e75 (2018).
Fonseca-Ornelas, L. et al. Parkinson-causing mutations in LRRK2 impair the physiological tetramerization of endogenous α-synuclein in human neurons. npj Parkinsons Dis. 8, 118 (2022).
Glajch, K. E. et al. Wild-type GBA1 increases the α-synuclein tetramer–monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2103425118 (2021).
Kim, S. et al. GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers. Proc. Natl Acad. Sci. USA 115, 798–803 (2018).
de Boni, L. et al. Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by α-synuclein conformations. Acta Neuropathol. 143, 453–469 (2022).
Wang, L. et al. α-Synuclein multimers cluster synaptic vesicles and attenuate recycling. Curr. Biol. 24, 2319–2326 (2014).
Fauvet, B. et al. α-Synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J. Biol. Chem. 287, 15345–15364 (2012).
Lee, H. J., Choi, C. & Lee, S. J. Membrane-bound α-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form. J. Biol. Chem. 277, 671–678 (2002).
Zhu, M., Li, J. & Fink, A. L. The association of α-synuclein with membranes affects bilayer structure, stability, and fibril formation. J. Biol. Chem. 278, 40186–40197 (2003).
Dikiy, I. & Eliezer, D. Folding and misfolding of α-synuclein on membranes. Biochim. Biophys. Acta 1818, 1013–1018 (2012).
Cui, H., Lyman, E. & Voth, G. A. Mechanism of membrane curvature sensing by amphipathic helix containing proteins. Biophys. J. 100, 1271–1279 (2011).
Jensen, M. B. et al. Membrane curvature sensing by amphipathic helices: a single liposome study using α-synuclein and annexin B12. J. Biol. Chem. 286, 42603–42614 (2011).
Nuscher, B. et al. α-Synuclein has a high affinity for packing defects in a bilayer membrane: a thermodynamics study. J. Biol. Chem. 279, 21966–21975 (2004).
Rovere, M. et al. E46K-like α-synuclein mutants increase lipid interactions and disrupt membrane selectivity. J. Biol. Chem. 294, 9799–9812 (2019).
Clayton, D. F. & George, J. M. The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci. 21, 249–254 (1998).
Pranke, I. M. et al. α-Synuclein and ALPS motifs are membrane curvature sensors whose contrasting chemistry mediates selective vesicle binding. J. Cell Biol. 194, 89–103 (2011).
Fusco, G. et al. Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour. Nat. Commun. 5, 3827 (2014).
Ouberai, M. M. et al. α-Synuclein senses lipid packing defects and induces lateral expansion of lipids leading to membrane remodeling. J. Biol. Chem. 288, 20883–20895 (2013).
Varkey, J. et al. Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins. J. Biol. Chem. 285, 32486–32493 (2010).
Mizuno, N. et al. Remodeling of lipid vesicles into cylindrical micelles by α-synuclein in an extended α-helical conformation. J. Biol. Chem. 287, 29301–29311 (2012).
Jiang, Z., de Messieres, M. & Lee, J. C. Membrane remodeling by α-synuclein and effects on amyloid formation. J. Am. Chem. Soc. 135, 15970–15973 (2013).
Shi, Z., Sachs, J. N., Rhoades, E. & Baumgart, T. Biophysics of α-synuclein induced membrane remodelling. Phys. Chem. Chem. Phys. 17, 15561–15568 (2015).
Braun, A. R., Lacy, M. M., Ducas, V. C., Rhoades, E. & Sachs, J. N. α-Synuclein-induced membrane remodeling is driven by binding affinity, partition depth, and interleaflet order asymmetry. J. Am. Chem. Soc. 136, 9962–9972 (2014).
Madine, J., Doig, A. J. & Middleton, D. A. A study of the regional effects of α-synuclein on the organization and stability of phospholipid bilayers. Biochemistry 45, 5783–5792 (2006).
Peeters, B. W. A., Piet, A. C. A. & Fornerod, M. Generating membrane curvature at the nuclear pore: a lipid point of view. Cells https://doi.org/10.3390/cells11030469 (2022).
McMahon, H. T. & Boucrot, E. Membrane curvature at a glance. J. Cell Sci. 128, 1065–1070 (2015).
Adamczyk, A., Kacprzak, M. & Kazmierczak, A. α-Synuclein decreases arachidonic acid incorporation into rat striatal synaptoneurosomes. Folia Neuropathol. 45, 230–235 (2007).
Sharon, R., Bar-Joseph, I., Mirick, G. E., Serhan, C. N. & Selkoe, D. J. Altered fatty acid composition of dopaminergic neurons expressing α-synuclein and human brains with α-synucleinopathies. J. Biol. Chem. 278, 49874–49881 (2003).
Jo, E., Fuller, N., Rand, R. P., St George-Hyslop, P. & Fraser, P. E. Defective membrane interactions of familial Parkinson’s disease mutant A30P α-synuclein. J. Mol. Biol. 315, 799–807 (2002).
Choi, W. et al. Mutation E46K increases phospholipid binding and assembly into filaments of human α-synuclein. FEBS Lett. 576, 363–368 (2004).
Fiske, M. et al. Familial Parkinson’s disease mutant E46K α-synuclein localizes to membranous structures, forms aggregates, and induces toxicity in yeast models. ISRN Neurol. 2011, 521847 (2011).
Kiely, A. P. et al. Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation. Mol. Neurodegener. 10, 41 (2015).
Fares, M. B. et al. The novel Parkinson’s disease linked mutation G51D attenuates in vitro aggregation and membrane binding of α-synuclein, and enhances its secretion and nuclear localization in cells. Hum. Mol. Genet. 23, 4491–4509 (2014).
Perlmutter, J. D., Braun, A. R. & Sachs, J. N. Curvature dynamics of α-synuclein familial Parkinson disease mutants: molecular simulations of the micelle- and bilayer-bound forms. J. Biol. Chem. 284, 7177–7189 (2009).
Tsigelny, I. F. et al. Molecular determinants of α-synuclein mutants’ oligomerization and membrane interactions. ACS Chem. Neurosci. 6, 403–416 (2015).
Maroteaux, L., Campanelli, J. T. & Scheller, R. H. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J. Neurosci. 8, 2804–2815 (1988).
Busch, D. J. et al. Acute increase of α-synuclein inhibits synaptic vesicle recycling evoked during intense stimulation. Mol. Biol. Cell 25, 3926–3941 (2014).
Snead, D. & Eliezer, D. α-Synuclein function and dysfunction on cellular membranes. Exp. Neurobiol. 23, 292–313 (2014).
George, J. M., Jin, H., Woods, W. S. & Clayton, D. F. Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15, 361–372 (1995).
Lautenschlager, J. et al. C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction. Nat. Commun. 9, 712 (2018).
Burre, J., Sharma, M. & Sudhof, T. C. Systematic mutagenesis of α-synuclein reveals distinct sequence requirements for physiological and pathological activities. J. Neurosci. 32, 15227–15242 (2012).
Burre, J. et al. α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329, 1663–1667 (2010).
Yoo, G., Yeou, S., Son, J. B., Shin, Y. K. & Lee, N. K. Cooperative inhibition of SNARE-mediated vesicle fusion by α-synuclein monomers and oligomers. Sci. Rep. 11, 10955 (2021).
Kaur, U. & Lee, J. C. Unroofing site-specific α-synuclein–lipid interactions at the plasma membrane. Proc. Natl Acad. Sci. USA 117, 18977–18983 (2020).
Lou, X., Kim, J., Hawk, B. J. & Shin, Y. K. α-Synuclein may cross-bridge v-SNARE and acidic phospholipids to facilitate SNARE-dependent vesicle docking. Biochem. J. 474, 2039–2049 (2017).
Lai, Y. et al. Nonaggregated α-synuclein influences SNARE-dependent vesicle docking via membrane binding. Biochemistry 53, 3889–3896 (2014).
Diao, J. et al. Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2. eLife 2, e00592 (2013).
DeWitt, D. C. & Rhoades, E. α-Synuclein can inhibit SNARE-mediated vesicle fusion through direct interactions with lipid bilayers. Biochemistry 52, 2385–2387 (2013).
Nemani, V. M. et al. Increased expression of α-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65, 66–79 (2010).
Sulzer, D. & Edwards, R. H. The physiological role of α-synuclein and its relationship to Parkinson’s Disease. J. Neurochem. 150, 475–486 (2019).
Bridi, J. C. & Hirth, F. Mechanisms of α-synuclein induced synaptopathy in Parkinson’s disease. Front. Neurosci. 12, 80 (2018).
Logan, T., Bendor, J., Toupin, C., Thorn, K. & Edwards, R. H. α-Synuclein promotes dilation of the exocytotic fusion pore. Nat. Neurosci. 20, 681–689 (2017).
Darios, F. et al. α-Synuclein sequesters arachidonic acid to modulate SNARE-mediated exocytosis. EMBO Rep. 11, 528–533 (2010).
Fonseca-Ornelas, L. et al. Altered conformation of α-synuclein drives dysfunction of synaptic vesicles in a synaptosomal model of Parkinson’s disease. Cell Rep. 36, 109333 (2021).
Atias, M. et al. Synapsins regulate α-synuclein functions. Proc. Natl Acad. Sci. USA 116, 11116–11118 (2019).
Medeiros, A. T., Soll, L. G., Tessari, I., Bubacco, L. & Morgan, J. R. α-Synuclein dimers impair vesicle fission during clathrin-mediated synaptic vesicle recycling. Front. Cell Neurosci. 11, 388 (2017).
Vargas, K. J. et al. Synucleins have multiple effects on presynaptic architecture. Cell Rep. 18, 161–173 (2017).
Fortin, D. L. et al. Neural activity controls the synaptic accumulation of α-synuclein. J. Neurosci. 25, 10913–10921 (2005).
Fortin, D. L. et al. Lipid rafts mediate the synaptic localization of α-synuclein. J. Neurosci. 24, 6715–6723 (2004).
Sun, J. et al. Functional cooperation of α-synuclein and VAMP2 in synaptic vesicle recycling. Proc. Natl Acad. Sci. USA 116, 11113–11115 (2019).
Lundblad, M., Decressac, M., Mattsson, B. & Bjorklund, A. Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons. Proc. Natl Acad. Sci. USA 109, 3213–3219 (2012).
Cabin, D. E. et al. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking α-synuclein. J. Neurosci. 22, 8797–8807 (2002).
Fusco, G. et al. Structural basis of synaptic vesicle assembly promoted by α-synuclein. Nat. Commun. 7, 12563 (2016).
Takamori, S. et al. Molecular anatomy of a trafficking organelle. Cell 127, 831–846 (2006).
Michaelson, D. M., Barkai, G. & Barenholz, Y. Asymmetry of lipid organization in cholinergic synaptic vesicle membranes. Biochem. J. 211, 155–162 (1983).
Brenna, J. T. & Carlson, S. E. Docosahexaenoic acid and human brain development: evidence that a dietary supply is needed for optimal development. J. Hum. Evol. 77, 99–106 (2014).
Fujita, S., Ikegaya, Y., Nishikawa, M., Nishiyama, N. & Matsuki, N. Docosahexaenoic acid improves long-term potentiation attenuated by phospholipase A(2) inhibitor in rat hippocampal slices. Br. J. Pharmacol. 132, 1417–1422 (2001).
Tanaka, K., Farooqui, A. A., Siddiqi, N. J., Alhomida, A. S. & Ong, W. Y. Effects of docosahexaenoic acid on neurotransmission. Biomol. Therap. 20, 152–157 (2012).
Harauma, A. et al. The essentiality of arachidonic acid in addition to docosahexaenoic acid for brain growth and function. Prostagland. Leukotrienes Essent. Fat. Acids 116, 9–18 (2017).
Wang, B. et al. Signal Transduction and Targeted Therapy Vol. 6 (Springer Nature, 2021).
Cao, D. et al. Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function. J. Neurochem. 111, 510–521 (2009).
Singh, M. Essential fatty acids, DHA and human brain. Ind. J. Pediatr. 72, 239–242 (2005).
Wurtman, R. J. Synapse formation and cognitive brain development: effect of docosahexaenoic acid and other dietary constituents. Metabolism 57(Suppl. 2), S6–S10 (2008).
Simon-Sanchez, J. et al. Genome-wide association study confirms extant PD risk loci among the Dutch. Eur. J. Hum. Genet. 19, 655–661 (2011).
Mata, I. F. et al. SNCA variant associated with Parkinson disease and plasma α-synuclein level. Arch. Neurol. 67, 1350–1356 (2010).
Blauwendraat, C. et al. Parkinson’s disease age at onset genome-wide association study: defining heritability, genetic loci, and α-synuclein mechanisms. Mov. Disord. 34, 866–875 (2019).
Foo, J. N. et al. Identification of risk loci for Parkinson disease in Asians and comparison of risk between Asians and Europeans: a genome-wide association study. JAMA Neurol. 77, 746–754 (2020).
Pan, H. et al. Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson’s disease in Chinese population. npj Parkinsons Dis. 9, 22 (2023).
Do, C. B. et al. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease. PLoS Genet. 7, e1002141 (2011).
Kim, J. J. et al. Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease. Nat. Genet. https://doi.org/10.1038/s41588-023-01584-8 (2023).
Jung, S. Y., Jeon, H. K., Choi, J. S. & Kim, Y. J. Reduced expression of FASN through SREBP-1 down-regulation is responsible for hypoxic cell death in HepG2 cells. J. Cell. Biochem. 113, 3730–3739 (2012).
Li, G. et al. Association of GALC, ZNF184, IL1R2 and ELOVL7 with Parkinson’s disease in Southern Chinese. Front. Aging Neurosci. 10, 402 (2018).
Keo, A. et al. Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease. Commun. Biol. 3, 101 (2020).
Naganuma, T., Sato, Y., Sassa, T., Ohno, Y. & Kihara, A. Biochemical characterization of the very long-chain fatty acid elongase ELOVL7. FEBS Lett. 585, 3337–3341 (2011).
Malaguti, M. C. et al. A novel homozygous PLA2G6 mutation causes dystonia-parkinsonism. Parkinsonism Relat. Disord. 21, 337–339 (2015).
Morgan, N. V. et al. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat. Genet. 38, 752–754 (2006).
Mori, A. et al. Parkinson’s disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling. Proc. Natl Acad. Sci. USA 116, 20689–20699 (2019).
Shen, T. et al. Early-onset Parkinson’s disease caused by PLA2G6 compound heterozygous mutation, a case report and literature review. Front. Neurol. 10, 915 (2019).
Yamashita, C. et al. Mutation screening of PLA2G6 in Japanese patients with early onset dystonia-parkinsonism. J. Neural Transm. 124, 431–435 (2017).
Gui, Y. X. et al. Four novel rare mutations of PLA2G6 in Chinese population with Parkinson’s disease. Parkinsonism Relat. Disord. 19, 21–26 (2013).
Rappley, I. et al. Evidence that α-synuclein does not inhibit phospholipase D. Biochemistry 48, 1077–1083 (2009).
Gorbatyuk, O. S. et al. α-Synuclein expression in rat substantia nigra suppresses phospholipase D2 toxicity and nigral neurodegeneration. Mol. Ther. 18, 1758–1768 (2010).
Mendez-Gomez, H. R. et al. The lipase activity of phospholipase D2 is responsible for nigral neurodegeneration in a rat model of Parkinson’s disease. Neuroscience 377, 174–183 (2018).
Bae, E. J. et al. Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates. Cell Death Differ. 21, 1132–1141 (2014).
Conde, M. A. et al. Phospholipase D1 downregulation by α-synuclein: implications for neurodegeneration in Parkinson’s disease. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1863, 639–650 (2018).
Gatarek, P. et al. Plasma metabolic disturbances in Parkinson’s disease patients. Biomedicines https://doi.org/10.3390/biomedicines10123005 (2022).
Hu, W. et al. Metabolic profiling reveals circulating biomarkers associated with incident and prevalent Parkinson’s disease. npj Parkinsons Dis. 10, 130 (2024).
Zhang, J. et al. Targeted fatty acid metabolomics to discover Parkinson’s disease associated metabolic alteration. J. Mass Spectrom. 56, e4781 (2021).
Willkommen, D. et al. Metabolomic investigations in cerebrospinal fluid of Parkinson’s disease. PLoS ONE 13, e0208752 (2018).
Trupp, M. et al. Metabolite and peptide levels in plasma and CSF differentiating healthy controls from patients with newly diagnosed Parkinson’s disease. J. Parkinsons Dis. 4, 549–560 (2014).
Zhao, H. et al. Potential biomarkers of Parkinson’s disease revealed by plasma metabolic profiling. J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 1081–1082, 101–108 (2018).
LeWitt, P. A. et al. Metabolomic biomarkers as strong correlates of Parkinson disease progression. Neurology 88, 862–869 (2017).
Chistyakov, D. V. et al. Plasma oxylipin profiles reflect Parkinson’s disease stage. Prostaglandins Other Lipid Mediat. 171, 106788 (2024).
Abbott, S. K. et al. Fatty acid composition of the anterior cingulate cortex indicates a high susceptibility to lipid peroxidation in Parkinson’s disease. J. Parkinsons Dis. 5, 175–185 (2015).
Dalfo, E. et al. Evidence of oxidative stress in the neocortex in incidental Lewy body disease. J. Neuropathol. Exp. Neurol. 64, 816–830 (2005).
Eijsvogel, P. P. N. M. et al. Fatty acids as potential biomarkers of stearoyl-CoA desaturase inhibition: variation in healthy subjects and Parkinson’s disease patients. Biomark. Neuropsychiatr. 13, 100132 (2025).
Terry-Kantor, E. et al. Rapid α-synuclein toxicity in a neural cell model and its rescue by a stearoyl-CoA desaturase inhibitor. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21155193 (2020).
Heman-Ackah, S. M. et al. α-Synuclein induces the unfolded protein response in Parkinson’s disease SNCA triplication iPSC-derived neurons. Hum. Mol. Genet. 26, 4441–4450 (2017).
Maulik, M. et al. Genetic silencing of fatty acid desaturases modulates α-synuclein toxicity and neuronal loss in Parkinson-like models of C. elegans. Front. Aging Neurosci. 11, 207 (2019).
Tardiff, D. F. et al. Non-clinical pharmacology of YTX-7739: a clinical stage stearoyl-CoA desaturase inhibitor being developed for Parkinson’s disease. Mol. Neurobiol. 59, 2171–2189 (2022).
Adom, M. A. et al. Reducing the lipase LIPE in mutant α-synuclein mice improves Parkinson-like deficits and reveals sex differences in fatty acid metabolism. Neurobiol. Dis. 199, 106593 (2024).
Bousquet, M., Calon, F. & Cicchetti, F. Impact of omega-3 fatty acids in Parkinson’s disease. Ageing Res. Rev. 10, 453–463 (2011).
Li, P. & Song, C. Potential treatment of Parkinson’s disease with omega-3 polyunsaturated fatty acids. Nutr. Neurosci. 25, 180–191 (2022).
Fecchio, C., Palazzi, L. & de Laureto, P. P. α-Synuclein and polyunsaturated fatty acids: molecular basis of the interaction and implication in neurodegeneration. Molecules 23, 1531 (2018).
Alves, B. D. S., Schimith, L. E., da Cunha, A. B., Dora, C. L. & Hort, M. A. Omega-3 polyunsaturated fatty acids and Parkinson’s disease: a systematic review of animal studies. J. Neurochem. 168, 1655–1683 (2024).
Vos, M. et al. Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency. J. Cell Biol. 216, 695–708 (2017).
Duan, W. X., Wang, F., Liu, J. Y. & Liu, C. F. Relationship between short-chain fatty acids and Parkinson’s disease: a review from pathology to clinic. Neurosci. Bull. https://doi.org/10.1007/s12264-023-01123-9 (2023).
Fitzner, D. et al. Cell-type- and brain-region-resolved mouse brain lipidome. Cell Rep. 32, 108132 (2020).
Osetrova, M. et al. Lipidome atlas of the adult human brain. Nat. Commun. 15, 4455 (2024).
Barber, C. N. & Raben, D. M. Lipid metabolism crosstalk in the brain: glia and neurons. Front. Cell. Neurosci. 13, 212 (2019).
Cleland, N. R. W. & Bruce, K. D. Fatty acid sensing in the brain: the role of glial-neuronal metabolic crosstalk and horizontal lipid flux. Biochimie 223, 166–178 (2024).
Ioannou, M. S. et al. Neuron–astrocyte metabolic coupling protects against activity-induced fatty acid toxicity. Cell 177, 1522–1535.e14 (2019).
Ioannou, M. S., Liu, Z. & Lippincott-Schwartz, J. A neuron-glia co-culture system for studying intercellular lipid transport. Curr. Protoc. Cell Biol. 84, e95 (2019).
de Lau, L. M. et al. Dietary fatty acids and the risk of Parkinson disease: the Rotterdam study. Neurology 64, 2040–2045 (2005).
Keramati, M., Kheirouri, S. & Etemadifar, M. Dietary approach to stop hypertension (DASH), but not Mediterranean and MIND, dietary pattern protects against Parkinson’s disease. Food Sci. Nutr. 12, 943–951 (2024).
Maraki, M. I. et al. Mediterranean diet is associated with a lower probability of prodromal Parkinson’s disease and risk for Parkinson’s disease/dementia with Lewy bodies: a longitudinal study. Eur. J. Neurol. 30, 934–942 (2023).
Xu, S., Li, W. & Di, Q. Association of dietary patterns with Parkinson’s disease: a cross-sectional study based on the United States National Health and Nutritional Examination Survey Database. Eur. Neurol. 86, 63–72 (2023).
Solch, R. J. et al. Mediterranean diet adherence, gut microbiota, and Alzheimer’s or Parkinson’s disease risk: a systematic review. J. Neurol. Sci. 434, 120166 (2022).
Alcalay, R. N. et al. The association between Mediterranean diet adherence and Parkinson’s disease. Mov. Disord. 27, 771–774 (2012).
Kamel, F. et al. Dietary fat intake, pesticide use, and Parkinson’s disease. Parkinsonism Relat. Disord. 20, 82–87 (2014).
Qu, Y., Chen, X., Xu, M. M. & Sun, Q. Relationship between high dietary fat intake and Parkinson’s disease risk: a meta-analysis. Neural Regen. Res. 14, 2156–2163 (2019).
Zimmer, L. et al. Modification of dopamine neurotransmission in the nucleus accumbens of rats deficient in n−3 polyunsaturated fatty acids. J. Lipid Res. 41, 32–40 (2000).
Chalon, S. et al. Dietary fish oil affects monoaminergic neurotransmission and behavior in rats. J. Nutr. 128, 2512–2519 (1998).
Vial, D. & Piomelli, D. Dopamine D2 receptors potentiate arachidonate release via activation of cytosolic, arachidonate-specific phospholipase A2. J. Neurochem. 64, 2765–2772 (1995).
Chang, J. P., Abele, J. T., Van Goor, F., Wong, A. O. & Neumann, C. M. Role of arachidonic acid and calmodulin in mediating dopamine D1- and GnRH-stimulated growth hormone release in goldfish pituitary cells. Gen. Comp. Endocrinol. 102, 88–101 (1996).
Yehuda, S., Rabinovitz, S., Carasso, R. L. & Mostofsky, D. I. Fatty acids and brain peptides. Peptides 19, 407–419 (1998).
Aharon-Peretz, J., Rosenbaum, H. & Gershoni-Baruch, R. Mutations in the glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N. Engl. J. Med. 351, 1972–1977 (2004).
Goker-Alpan, O. et al. Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology 67, 908–910 (2006).
Clark, L. N. et al. Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology 69, 1270–1277 (2007).
Nichols, W. C. et al. Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. Neurology 72, 310–316 (2009).
Robak, L. A. et al. Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease. Brain 140, 3191–3203 (2017).
Zhu, X. C. et al. Association of Parkinson’s disease GWAS-linked loci with Alzheimer’s disease in Han Chinese. Mol. Neurobiol. 54, 308–318 (2017).
Chen, Y. P. et al. GAK rs1564282 and DGKQ rs11248060 increase the risk for Parkinson’s disease in a Chinese population. J. Clin. Neurosci. 20, 880–883 (2013).
Quadri, M. et al. Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. Hum. Mutat. 34, 1208–1215 (2013).
Acknowledgements
The α-synuclein-related work of the authors is supported by NIH grants R01 NS083845 (to D.S.) and R01 133243 (to S.F.), the Michael J. Fox Foundation (to S.F.), The Ellison Foundation of Boston (to S.F.) and a philanthropic gift establishing the Karolinska–Harvard Collaboration on Parkinson’s Disease (to D.S.). The authors thank U. Dettmer, S. Nuber and G. Ho for helpful discussions.
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D.S. declares that he is a director and consultant for Prothena Biosciences and an ad hoc consultant for Roche and Eisai. S.F. declares that she is an ad hoc consultant for Janssen.
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Fanning, S., Selkoe, D. Parkinson disease is a fatty acidopathy. Nat Rev Neurol (2025). https://doi.org/10.1038/s41582-025-01142-2
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DOI: https://doi.org/10.1038/s41582-025-01142-2
