[en] There is a continued unmet need for treatments that can slow Parkinson's disease progression due to the lack of understanding behind the molecular mechanisms underlying neurodegeneration. Since its discovery, ferroptosis has been implicated in several diseases and represents a therapeutic target in Parkinson's disease. Here, we use two highly relevant human dopaminergic neuronal models to show that endogenous levels of α-synuclein can determine the sensitivity of dopaminergic neurons to ferroptosis. We show that reducing α-synuclein expression in dopaminergic neurons leads to ferroptosis evasion, while elevated α-synuclein expression in patients' small-molecule-derived neuronal precursor cells with SNCA triplication causes an increased vulnerability to lipid peroxidation and ferroptosis. Lipid profiling reveals that ferroptosis resistance is due to a reduction in ether-linked phospholipids, required for ferroptosis, in neurons depleted of α-synuclein (α-syn). These results provide a molecular mechanism linking α-syn levels to the sensitivity of dopaminergic neurons to ferroptosis, suggesting potential therapeutic relevance.
Disciplines :
Neurologie
Auteur, co-auteur :
Mahoney-Sanchez, Laura
Bouchaoui, Hind
BOUSSAAD, Ibrahim ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services
Jonneaux, Aurélie
Timmerman, Kelly
Berdeaux, Olivier
Ayton, Scott
KRÜGER, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Duce, James A.
Devos, David
Devedjian, Jean-Christophe
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
Alpha synuclein determines ferroptosis sensitivity in dopaminergic neurons via modulation of ether-phospholipid membrane composition.
Alim, I., Caulfield, J.T., Chen, Y., Swarup, V., Geschwind, D.H., Ivanova, E., Seravalli, J., Ai, Y., Sansing, L.H., Ste Marie, E.J., et al. Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell 177 (2019), 1262–1279.e25, 10.1016/j.cell.2019.03.032.
Angelova, P.R., Choi, M.L., Berezhnov, A.V., Horrocks, M.H., Hughes, C.D., De, S., Rodrigues, M., Yapom, R., Little, D., Dolt, K.S., et al. Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation. Cell Death Differ. 27 (2020), 2781–2796, 10.1038/s41418-020-0542-z.
Ayton, S., Lei, P., Hare, D.J., Duce, J.A., George, J.L., Adlard, P.A., McLean, C., Rogers, J.T., Cherny, R.A., Finkelstein, D.I., Bush, A.I., Parkinson's disease iron deposition caused by nitric oxide-induced loss of β-amyloid precursor protein. J. Neurosci. 35 (2015), 3591–3597, 10.1523/JNEUROSCI.3439-14.2015.
Baksi, S., Singh, N., α-Synuclein impairs ferritinophagy in the retinal pigment epithelium: implications for retinal iron dyshomeostasis in Parkinson's disease. Sci. Rep., 7, 2017, 12843, 10.1038/s41598-017-12862-x.
Baksi, S., Tripathi, A.K., Singh, N., Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: implications for visual manifestations of Parkinson's disease. Free Radic. Biol. Med. 97 (2016), 292–306, 10.1016/j.freeradbiomed.2016.06.025.
Barbuti, P., Antony, P., Santos, B., Massart, F., Cruciani, G., Dording, C., Arias, J., Schwamborn, J., Krüger, R., Using high-content screening to generate single-cell gene-corrected patient-derived iPS clones reveals excess alpha-synuclein with familial Parkinson's disease point mutation A30P. Cells, 9, 2020, 2065, 10.3390/cells9092065.
Barbuti, P.A., Santos, B.F.R., Dording, C.M., Cruciani, G., Massart, F., Hummel, A., Krüger, R., Generation of two iPS cell lines (HIHDNDi001-A and HIHDNDi001-B) from a Parkinson's disease patient carrying the heterozygous p.A30P mutation in SNCA. Stem Cell Res., 48, 2020, 101951, 10.1016/j.scr.2020.101951.
Barceló-Coblijn, G., Golovko, M.Y., Weinhofer, I., Berger, J., Murphy, E.J., Brain neutral lipids mass is increased in alpha-synuclein gene-ablated mice. J. Neurochem. 101 (2007), 132–141, 10.1111/j.1471-4159.2006.04348.x.
Battino, M., Littarru, G.P., Gorini, A., Villa, R.F., Coenzyme Q, peroxidation and cytochrome oxidase features after Parkinson's-like disease by MPTP toxicity in intra-synaptic and non-synaptic mitochondria from Macaca fascicularis cerebral cortex and hippocampus: action of dihydroergocriptine. Neurochem. Res. 21 (1996), 1505–1514, 10.1007/BF02533098.
Bersuker, K., Hendricks, J.M., Li, Z., Magtanong, L., Ford, B., Tang, P.H., Roberts, M.A., Tong, B., Maimone, T.J., Zoncu, R., et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575 (2019), 688–692, 10.1038/s41586-019-1705-2.
Blauwendraat, C., Heilbron, K., Vallerga, C.L., Bandres-Ciga, S., von Coelln, R., Pihlstrøm, L., Simón-Sánchez, J., Schulte, C., Sharma, M., Krohn, L., et al. Parkinson's disease age at onset genome-wide association study: defining heritability, genetic loci, and α-synuclein mechanisms. Mov. Disord. 34 (2019), 866–875, 10.1002/mds.27659.
Bonifati, V., Rizzu, P., van Baren, M.J., Schaap, O., Breedveld, G.J., Krieger, E., Dekker, M.C.J., Squitieri, F., Ibanez, P., Joosse, M., et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299 (2003), 256–259, 10.1126/science.1077209.
Boussaad, I., Obermaier, C.D., Hanss, Z., Bobbili, D.R., Bolognin, S., Glaab, E., Wołyńska, K., Weisschuh, N., De Conti, L., May, C., et al. A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease. Sci. Transl. Med., 12, 2020, eaau3960, 10.1126/scitranslmed.aau3960.
Brites, P., Waterham, H.R., Wanders, R.J.A., Functions and biosynthesis of plasmalogens in health and disease. Biochim. Biophys. Acta 1636 (2004), 219–231, 10.1016/j.bbalip.2003.12.010.
Broersen, K., van den Brink, D., Fraser, G., Goedert, M., Davletov, B., Alpha-synuclein adopts an alpha-helical conformation in the presence of polyunsaturated fatty acids to hinder micelle formation. Biochemistry 45 (2006), 15610–15616, 10.1021/bi061743l.
Cao, J., Chen, X., Jiang, L., Lu, B., Yuan, M., Zhu, D., Zhu, H., He, Q., Yang, B., Ying, M., DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase. Nat. Commun., 11, 2020, 1251, 10.1038/s41467-020-15109-y.
Cui, W., Liu, D., Gu, W., Chu, B., Peroxisome-driven ether-linked phospholipids biosynthesis is essential for ferroptosis. Cell Death Differ. 28 (2021), 2536–2551, 10.1038/s41418-021-00769-0.
de Farias, C.C., Maes, M., Bonifácio, K.L., Bortolasci, C.C., de Souza Nogueira, A., Brinholi, F.F., Matsumoto, A.K., do Nascimento, M.A., de Melo, L.B., Nixdorf, S.L., et al. Highly specific changes in antioxidant levels and lipid peroxidation in Parkinson's disease and its progression: disease and staging biomarkers and new drug targets. Neurosci. Lett. 617 (2016), 66–71, 10.1016/j.neulet.2016.02.011.
De Franceschi, G., Frare, E., Bubacco, L., Mammi, S., Fontana, A., de Laureto, P.P., Molecular insights into the interaction between alpha-synuclein and docosahexaenoic acid. J. Mol. Biol. 394 (2009), 94–107, 10.1016/j.jmb.2009.09.008.
Devos, D., Moreau, C., Devedjian, J.C., Kluza, J., Petrault, M., Laloux, C., Jonneaux, A., Ryckewaert, G., Garçon, G., Rouaix, N., et al. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. Antioxid. Redox Signal. 21 (2014), 195–210, 10.1089/ars.2013.5593.
Devos, D., Moreau, C., Kyheng, M., Garçon, G., Rolland, A.S., Blasco, H., Gelé, P., Timothée Lenglet, T., Veyrat-Durebex, C., Corcia, P., et al. A ferroptosis–based panel of prognostic biomarkers for Amyotrophic Lateral Sclerosis. Sci. Rep. 9 (2019), 2918–2926, 10.1038/s41598-019-39739-5.
Dexter, D., Carter, C., Agid, F., Agid, Y., Lees, A.J., Jenner, P., Marsden, C.D., Lipid peroxidation as cause of nigral cell death in Parkinson's disease. Lancet 2 (1986), 639–640, 10.1016/s0140-6736(86)92471-2.
Dexter, D.T., Wells, F.R., Lees, A.J., Agid, F., Agid, Y., Jenner, P., Marsden, C.D., Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson's disease. J. Neurochem. 52 (1989), 1830–1836, 10.1111/j.1471-4159.1989.tb07264.x.
Dexter, D.T., Carter, C.J., Wells, F.R., Javoy-Agid, F., Agid, Y., Lees, A., Jenner, P., Marsden, C.D., Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J. Neurochem. 52 (1989), 381–389, 10.1111/j.1471-4159.1989.tb09133.x.
Di Domenico, F., Tramutola, A., Butterfield, D.A., Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders. Free Radic. Biol. Med. 111 (2017), 253–261, 10.1016/j.freeradbiomed.2016.10.490.
Dixon, S.J., Lemberg, K.M., Lamprecht, M.R., Skouta, R., Zaitsev, E.M., Gleason, C.E., Patel, D.N., Bauer, A.J., Cantley, A.M., Yang, W.S., et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149 (2012), 1060–1072, 10.1016/j.cell.2012.03.042.
Do Van, B., Gouel, F., Jonneaux, A., Timmerman, K., Gelé, P., Pétrault, M., Bastide, M., Laloux, C., Moreau, C., Bordet, R., et al. Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC. Neurobiol. Dis. 94 (2016), 169–178, 10.1016/j.nbd.2016.05.011.
Doll, S., Proneth, B., Tyurina, Y.Y., Panzilius, E., Kobayashi, S., Ingold, I., Irmler, M., Beckers, J., Aichler, M., Walch, A., et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13 (2017), 91–98, 10.1038/nchembio.2239.
Eichmann, C., Kumari, P., Riek, R., High-density lipoprotein-like particle formation of Synuclein variants. FEBS Lett. 591 (2017), 304–311, 10.1002/1873-3468.12543.
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, 2018, E1531, 10.3390/molecules23071531.
Folch, J., Lees, M., Sloane Stanley, G.H., A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226 (1957), 497–509.
Ford, D.A., Hazen, S.L., Saffitz, J.E., Gross, R.W., The rapid and reversible activation of a calcium-independent plasmalogen-selective phospholipase A2 during myocardial ischemia. J. Clin. Invest. 88 (1991), 331–335, 10.1172/JCI115296.
Friedmann Angeli, J.P., Schneider, M., Proneth, B., Tyurina, Y.Y., Tyurin, V.A., Hammond, V.J., Herbach, N., Aichler, M., Walch, A., Eggenhofer, E., et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16 (2014), 1180–1191, 10.1038/ncb3064.
Galluzzi, L., Vitale, I., Aaronson, S.A., Abrams, J.M., Adam, D., Agostinis, P., Alnemri, E.S., Altucci, L., Amelio, I., Andrews, D.W., et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 25 (2018), 486–541, 10.1038/s41418-017-0012-4.
Golovko, M.Y., Faergeman, N.J., Cole, N.B., Castagnet, P.I., Nussbaum, R.L., Murphy, E.J., Alpha-synuclein gene deletion decreases brain palmitate uptake and alters the palmitate metabolism in the absence of alpha-synuclein palmitate binding. Biochemistry 44 (2005), 8251–8259, 10.1021/bi0502137.
Golovko, M.Y., Rosenberger, T.A., Faergeman, N.J., Feddersen, S., Cole, N.B., Pribill, I., Berger, J., Nussbaum, R.L., Murphy, E.J., Acyl-CoA synthetase activity links wild-type but not mutant alpha-synuclein to brain arachidonate metabolism. Biochemistry 45 (2006), 6956–6966, 10.1021/bi0600289.
Golovko, M.Y., Rosenberger, T.A., Feddersen, S., Faergeman, N.J., Murphy, E.J., Alpha-synuclein gene ablation increases docosahexaenoic acid incorporation and turnover in brain phospholipids. J. Neurochem. 101 (2007), 201–211, 10.1111/j.1471-4159.2006.04357.x.
Guiney, S.J., Adlard, P.A., Bush, A.I., Finkelstein, D.I., Ayton, S., Ferroptosis and cell death mechanisms in Parkinson's disease. Neurochem. Int. 104 (2017), 34–48, 10.1016/j.neuint.2017.01.004.
Hirsch, E.C., Brandel, J.P., Galle, P., Javoy-Agid, F., Agid, Y., Iron and aluminum increase in the substantia nigra of patients with Parkinson's disease: an X-ray microanalysis. J. Neurochem. 56 (1991), 446–451, 10.1111/j.1471-4159.1991.tb08170.x.
Karuppagounder, S.S., Alin, L., Chen, Y., Brand, D., Bourassa, M.W., Dietrich, K., Wilkinson, C.M., Nadeau, C.A., Kumar, A., Perry, S., et al. N-acetylcysteine targets 5 lipoxygenase-derived, toxic lipids and can synergize with prostaglandin E2 to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice. Ann. Neurol. 84 (2018), 854–872, 10.1002/ana.25356.
Li, Y., Maher, P., Schubert, D., A role for 12-lipoxygenase in nerve cell death caused by glutathione depletion. Neuron 19 (1997), 453–463, 10.1016/s0896-6273(00)80953-8.
Linkermann, A., Skouta, R., Himmerkus, N., Mulay, S.R., Dewitz, C., De Zen, F., Prokai, A., Zuchtriegel, G., Krombach, F., Welz, P.-S., et al. Synchronized renal tubular cell death involves ferroptosis. Proc. Natl. Acad. Sci. USA 111 (2014), 16836–16841, 10.1073/pnas.1415518111.
Magtanong, L., Ko, P.-J., To, M., Cao, J.Y., Forcina, G.C., Tarangelo, A., Ward, C.C., Cho, K., Patti, G.J., Nomura, D.K., et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem. Biol. 26 (2019), 420–432.e9, 10.1016/j.chembiol.2018.11.016.
Mahoney-Sánchez, L., Bouchaoui, H., Ayton, S., Devos, D., Duce, J.A., Devedjian, J.-C., Ferroptosis and its potential role in the physiopathology of Parkinson's Disease. Prog. Neurobiol., 196, 2020, 10.1016/j.pneurobio.2020.101890.
Martin-Sanchez, D., Ruiz-Andres, O., Poveda, J., Carrasco, S., Cannata-Ortiz, P., Sanchez-Niño, M.D., Ruiz Ortega, M., Egido, J., Linkermann, A., Ortiz, A., Sanz, A.B., Ferroptosis, but not necroptosis, is important in nephrotoxic folic acid-induced AKI. J. Am. Soc. Nephrol. 28 (2017), 218–229, 10.1681/ASN.2015121376.
Mischley, L.K., Allen, J., Bradley, R., Coenzyme Q10 deficiency in patients with Parkinson's disease. J. Neurol. Sci. 318 (2012), 72–75, 10.1016/j.jns.2012.03.023.
Mohamed, N.-V., Sirois, J., Ramamurthy, J., Mathur, M., Lépine, P., Deneault, E., Maussion, G., Nicouleau, M., Chen, C.X.-Q., Abdian, N., et al. Midbrain organoids with an SNCA gene triplication model key features of synucleinopathy. Brain Commun., 3, 2021, fcab223, 10.1093/braincomms/fcab223.
Moreau, C., Duce, J.A., Rascol, O., Devedjian, J.-C., Berg, D., Dexter, D., Cabantchik, Z.I., Bush, A.I., Devos, D., FAIRPARK-II study group. Iron as a therapeutic target for Parkinson's disease. Mov. Disord. 33 (2018), 568–574, 10.1002/mds.27275.
Naudí, A., Cabré, R., Dominguez-Gonzalez, M., Ayala, V., Jové, M., Mota-Martorell, N., Piñol-Ripoll, G., Gil-Villar, M.P., Rué, M., Portero-Otín, M., et al. Region-specific vulnerability to lipid peroxidation and evidence of neuronal mechanisms for polyunsaturated fatty acid biosynthesis in the healthy adult human central nervous system. Biochim. Biophys. Acta. Mol. Cell Biol. Lipids, 2017, 485–495, 10.1016/j.bbalip.2017.02.001.
Pearce, R.K., Owen, A., Daniel, S., Jenner, P., Marsden, C.D., Alterations in the distribution of glutathione in the substantia nigra in Parkinson's disease. J. Neural. Transm. 104 (1997), 661–677, 10.1007/BF01291884.
Schneider, S.A., Obeso, J.A., Clinical and pathological features of Parkinson's disease. Curr. Top. Behav. Neurosci. 22 (2015), 205–220, 10.1007/7854_2014_317.
Sharon, R., Goldberg, M.S., Bar-Josef, I., Betensky, R.A., Shen, J., Selkoe, D.J., 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 (2001), 9110–9115, 10.1073/pnas.171300598.
Sharon, R., Bar-Joseph, I., Mirick, G.E., Serhan, C.N., Selkoe, D.J., Altered fatty acid composition of dopaminergic neurons expressing alpha-synuclein and human brains with alpha-synucleinopathies. J. Biol. Chem. 278 (2003), 49874–49881, 10.1074/jbc.M309127200.
Sian, J., Dexter, D.T., Lees, A.J., Daniel, S., Agid, Y., Javoy-Agid, F., Jenner, P., Marsden, C.D., Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. Ann. Neurol. 36 (1994), 348–355, 10.1002/ana.410360305.
Sofic, E., Lange, K.W., Jellinger, K., Riederer, P., Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson's disease. Neurosci. Lett. 142 (1992), 128–130, 10.1016/0304-3940(92)90355-b.
Spillantini, M.G., Schmidt, M.L., Lee, V.M., Trojanowski, J.Q., Jakes, R., Goedert, M., Alpha-synuclein in Lewy bodies. Nature 388 (1997), 839–840, 10.1038/42166.
Stockwell, B.R., Friedmann Angeli, J.P., Bayir, H., Bush, A.I., Conrad, M., Dixon, S.J., Fulda, S., Gascón, S., Hatzios, S.K., Kagan, V.E., et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171 (2017), 273–285, 10.1016/j.cell.2017.09.021.
Tang, D., Chen, X., Kang, R., Kroemer, G., Ferroptosis: molecular mechanisms and health implications. Cell Res. 31 (2021), 107–125, 10.1038/s41422-020-00441-1.
Vallerga, C.L., Zhang, F., Fowdar, J., McRae, A.F., Qi, T., Nabais, M.F., Zhang, Q., Kassam, I., Henders, A.K., Wallace, L., et al. Analysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson's disease. Nat. Commun., 11, 2020, 1238, 10.1038/s41467-020-15065-7.
Wolf, R.A., Gross, R.W., Identification of neutral active phospholipase C which hydrolyzes choline glycerophospholipids and plasmalogen selective phospholipase A2 in canine myocardium. J. Biol. Chem. 260 (1985), 7295–7303.
Yakunin, E., Kisos, H., Kulik, W., Grigoletto, J., Wanders, R.J.A., Sharon, R., The regulation of catalase activity by PPAR γ is affected by α -synuclein. Ann. Clin. Transl. Neurol. 1 (2014), 145–159, 10.1002/acn3.38.
Yang, W.S., Kim, K.J., Gaschler, M.M., Patel, M., Shchepinov, M.S., Stockwell, B.R., Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc. Natl. Acad. Sci. USA 113 (2016), E4966–E4975, 10.1073/pnas.1603244113.
Zhang, Y., Shu, L., Sun, Q., Pan, H., Guo, J., Tang, B., A comprehensive analysis of the association between SNCA polymorphisms and the risk of Parkinson's disease. Front. Mol. Neurosci., 11, 2018, 391, 10.3389/fnmol.2018.00391.
Zhang, Z., Wu, Y., Yuan, S., Zhang, P., Zhang, J., Li, H., Li, X., Shen, H., Wang, Z., Chen, G., Glutathione peroxidase 4 participates in secondary brain injury through mediating ferroptosis in a rat model of intracerebral hemorrhage. Brain Res. 1701 (2018), 112–125, 10.1016/j.brainres.2018.09.012.
Ziv, I., Shirvan, A., Offen, D., Barzilai, A., Melamed, E., Molecular biology of dopamine-induced apoptosis: possible implications for Parkinson's disease. Methods Mol. Med. 62 (2001), 73–87, 10.1385/1-59259-142-6:73.
