Role of Lipids in the Pathogenesis of Parkinson’s Disease
Abstract
:1. Introduction
2. Association between Lipids and αSyn Aggregation
3. αSyn and Lipids in Brain Tissue
4. Mutations in Lipid Metabolism-Associated Genes and PD Pathogenesis
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Bloem, B.R.; Okun, M.S.; Klein, C. Parkinson’s disease. Lancet 2021, 397, 2284–2303. [Google Scholar] [CrossRef] [PubMed]
- Spillantini, M.G.; Schmidt, M.L.; Lee, V.M.; Trojanowski, J.Q.; Jakes, R.; Goedert, M. α-Synuclein in Lewy bodies. Nature 1997, 388, 839–840. [Google Scholar] [CrossRef] [PubMed]
- Spillantini, M.G.; Crowther, R.A.; Jakes, R.; Cairns, N.J.; Lantos, P.L.; Goedert, M. Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci. Lett. 1998, 251, 205–208. [Google Scholar] [CrossRef] [PubMed]
- Spillantini, M.G.; Crowther, R.A.; Jakes, R.; Hasegawa, M.; Goedert, M. α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc. Natl. Acad. Sci. USA 1998, 95, 6469–6473. [Google Scholar] [CrossRef] [PubMed]
- Krüger, R.; Kuhn, W.; Muller, T.; Woitalla, D.; Graeber, M.; Kosel, S.; Przuntek, H.; Epplen, J.T.; Schols, L.; Riess, O. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat. Genet. 1998, 18, 106–108. [Google Scholar] [CrossRef] [PubMed]
- Zarranz, J.J.; Alegre, J.; Gomez-Esteban, J.C.; Lezcano, E.; Ros, R.; Ampuero, I.; Vidal, L.; Hoenicka, J.; Rodriguez, O.; Atares, B.; et al. The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 2004, 55, 164–173. [Google Scholar] [CrossRef] [PubMed]
- Appel-Cresswell, S.; Vilarino-Guell, C.; Encarnacion, M.; Sherman, H.; Yu, I.; Shah, B.; Weir, D.; Thompson, C.; Szu-Tu, C.; Trinh, J.; et al. Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson’s disease. Mov. Disord. 2013, 28, 811–813. [Google Scholar] [CrossRef] [PubMed]
- Proukakis, C.; Dudzik, C.G.; Brier, T.; MacKay, D.S.; Cooper, J.M.; Millhauser, G.L.; Houlden, H.; Schapira, A.H. A novel α-synuclein missense mutation in Parkinson disease. Neurology 2013, 80, 1062–1064. [Google Scholar] [CrossRef] [PubMed]
- Lesage, S.; Anheim, M.; Letournel, F.; Bousset, L.; Honore, A.; Rozas, N.; Pieri, L.; Madiona, K.; Durr, A.; Melki, R.; et al. G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann. Neurol. 2013, 73, 459–471. [Google Scholar] [CrossRef]
- Polymeropoulos, M.H. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 1997, 276, 2045–2047. [Google Scholar] [CrossRef]
- Pasanen, P.; Myllykangas, L.; Siitonen, M.; Raunio, A.; Kaakkola, S.; Lyytinen, J.; Tienari, P.J.; Poyhonen, M.; Paetau, A. Novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson’s disease-type pathology. Neurobiol. Aging 2014, 35, 2180.e1–2180.e5. [Google Scholar] [CrossRef]
- Singleton, A.B.; Farrer, M.; Johnson, J.; Singleton, A.; Hague, S.; Kachergus, J.; Hulihan, M.; Peuralinna, T.; Dutra, A.; Nussbaum, R.; et al. α-Synuclein locus triplication causes Parkinson’s disease. Science 2003, 302, 841. [Google Scholar] [CrossRef]
- Chartier-Harlin, M.C.; Kachergus, J.; Roumier, C.; Mouroux, V.; Douay, X.; Lincoln, S.; Levecque, C.; Larvor, L.; Andrieux, J.; Hulihan, M.; et al. α-Synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 2004, 364, 1167–1169. [Google Scholar] [CrossRef]
- Mueller, J.C.; Fuchs, J.; Hofer, A.; Zimprich, A.; Lichtner, P.; Illig, T.; Berg, D.; Wullner, U.; Meitinger, T.; Gasser, T. Multiple regions of α-synuclein are associated with Parkinson’s disease. Ann. Neurol. 2005, 57, 535–541. [Google Scholar] [CrossRef]
- Satake, W.; Nakabayashi, Y.; Mizuta, I.; Hirota, Y.; Ito, C.; Kubo, M.; Kawaguchi, T.; Tsunoda, T.; Watanabe, M.; Takeda, A.; et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat. Genet. 2009, 41, 1303–1307. [Google Scholar] [CrossRef]
- Simon-Sanchez, J.; Schulte, C.; Bras, J.M.; Sharma, M.; Gibbs, J.R.; Berg, D.; Paisan-Ruiz, C.; Lichtner, P.; Scholz, S.W.; Hernandez, D.G.; et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat. Genet. 2009, 41, 1308–1312. [Google Scholar] [CrossRef] [PubMed]
- Feany, M.B.; Bender, W.W. A Drosophila model of Parkinson’s disease. Nature 2000, 404, 394–398. [Google Scholar] [CrossRef]
- Lee, M.K.; Stirling, W.; Xu, Y.; Xu, X.; Qui, D.; Mandir, A.S.; Dawson, T.M.; Copeland, N.G.; Jenkins, N.A.; Price, D.L. Human α-synuclein-harboring familial Parkinson’s disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc. Natl. Acad. Sci. USA 2002, 99, 8968–8973. [Google Scholar] [CrossRef] [PubMed]
- Masliah, E.; Rockenstein, E.; Veinbergs, I.; Mallory, M.; Hashimoto, M.; Takeda, A.; Sagara, Y.; Sisk, A.; Mucke, L. Dopaminergic loss and inclusion body formation in α-synuclein mice: Implications for neurodegenerative disorders. Science 2000, 287, 1265–1269. [Google Scholar] [CrossRef] [PubMed]
- Conway, K.A.; Harper, J.D.; Lansbury, P.T. Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease. Nat. Med. 1998, 4, 1318–1320. [Google Scholar] [CrossRef]
- Uversky, V.N. Neuropathology, biochemistry, and biophysics of α-synuclein aggregation. J. Neurochem. 2007, 103, 17–37. [Google Scholar] [CrossRef] [PubMed]
- Sastry, P.S. Lipids of nervous tissue: Composition and metabolism. Prog. Lipid Res. 1985, 24, 69–176. [Google Scholar] [CrossRef] [PubMed]
- Farooqui, A.A.; Horrocks, L.A.; Farooqui, T. Glycerophospholipids in brain: Their metabolism, incorporation into membranes, functions, and involvement in neurological disorders. Chem. Phys. Lipids 2000, 106, 1–29. [Google Scholar] [CrossRef] [PubMed]
- Sorrentino, Z.A.; Giasson, B.I.; Chakrabarty, P. α-Synuclein and astrocytes: Tracing the pathways from homeostasis to neurodegeneration in Lewy body disease. Acta Neuropathol. 2019, 138, 1–21. [Google Scholar] [CrossRef] [PubMed]
- Castagnet, P.I.; Golovko, M.Y.; Barceló-Coblijn, G.C.; Nussbaum, R.L.; Murphy, E.J. Fatty acid incorporation is decreased in astrocytes cultured from alpha-synuclein gene-ablated mice. J Neurochem. 2005, 94, 839–849. [Google Scholar] [CrossRef] [PubMed]
- Galvagnion, C. The role of lipids interacting with α-synuclein in the pathogenesis of Parkinson’s disease. J. Park. Dis. 2017, 7, 433–450. [Google Scholar] [CrossRef] [PubMed]
- Sidransky, E.; Lopez, G. The link between the GBA gene and parkinsonism. Lancet Neurol. 2012, 11, 986–998. [Google Scholar] [CrossRef] [PubMed]
- Suzuki, M.; Fujikake, N.; Takeuchi, T.; Kohyama-Koganeya, A.; Nakajima, K.; Hirabayashi, Y.; Wada, K.; Nagai, Y. Glucocerebrosidase deficiency accelerates the accumulation of proteinase K-resistant α-synuclein and aggravates neurodegeneration in a Drosophila model of Parkinson’s disease. Hum. Mol. Genet. 2015, 24, 6675–6686. [Google Scholar] [CrossRef] [PubMed]
- Choong, C.J.; Aguirre, C.; Kakuda, K.; Beck, G.; Nakanishi, H.; Kimura, Y.; Shimma, S.; Nabekura, K.; Hideshima, M.; Doi, J.; et al. Phosphatidylinositol-3,4,5-trisphosphate interacts with alpha-synuclein and initiates its aggregation and formation of Parkinson’s disease-related fibril polymorphism. Acta Neuropathol. 2023, 145, 573–595. [Google Scholar] [CrossRef]
- Morgan, N.V.; Westaway, S.K.; Morton, J.E.; Gregory, A.; Gissen, P.; Sonek, S.; Cangul, H.; Coryell, J.; Canham, N.; Nardocci, N.; et al. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat. Genet. 2006, 38, 752–754. [Google Scholar] [CrossRef]
- Darvish, H.; Bravo, P.; Tafakhori, A.; Azcona, L.J.; Ranji-Burachaloo, S.; Johari, A.H.; Paisán-Ruiz, C. Identification of a large homozygous VPS13C deletion in a patient with early-onset Parkinsonism. Mov. Disord. 2018, 33, 1968–1970. [Google Scholar] [CrossRef] [PubMed]
- Illés, A.; Csabán, D.; Grosz, Z.; Balicza, P.; Gézsi, A.; Molnár, V.; Bencsik, R.; Gál, A.; Klivényi, P.; Molnar, M.J. The Role of Genetic Testing in the Clinical Practice and Research of Early-Onset Parkinsonian Disorders in a Hungarian Cohort: Increasing Challenge in Genetic Counselling, Improving Chances in Stratification for Clinical Trials. Front. Genet. 2019, 10, 1061. [Google Scholar] [CrossRef] [PubMed]
- Marshall, M.S.; Bongarzone, E.R. Beyond Krabbe’s disease: The potential contribution of galactosylceramidase deficiency to neuronal vulnerability in late-onset synucleinopathies. J. Neurosci. Res. 2016, 94, 1328–1332. [Google Scholar] [CrossRef] [PubMed]
- Araki, K.; Yagi, N.; Ikemoto, Y.; Yagi, H.; Choong, C.J.; Hayakawa, H.; Beck, G.; Sumi, H.; Fujimura, H.; Moriwaki, T.; et al. Synchrotron FTIR micro-spectroscopy for structural analysis of Lewy bodies in the brain of Parkinson’s disease patients. Sci. Rep. 2015, 5, 17625. [Google Scholar] [CrossRef]
- Lavedan, C.; Buchholtz, S.; Auburger, G.; Albin, R.L.; Athanassiadou, A.; Blancato, J.; Burguera, J.A.; Ferrell, R.E.; Kostic, V.; Leroy, E.; et al. Absence of mutation in the beta- and gamma-synuclein genes in familial autosomal dominant Parkinson’s disease. DNA Res. 1998, 5, 401–402. [Google Scholar] [CrossRef] [PubMed]
- 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 1995, 15, 361–372. [Google Scholar] [CrossRef] [PubMed]
- Iwai, A.; Masliah, E.; Yoshimoto, M.; Ge, N.; Flanagan, L.; de Silva, H.A.; Kittel, A.; Saitoh, T. The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 1995, 14, 467–475. [Google Scholar] [CrossRef]
- Maroteaux, L.; Campanelli, J.T.; Scheller, R.H. Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J. Neurosci. 1988, 8, 2804–2815. [Google Scholar] [CrossRef] [PubMed]
- Withers, G.S.; George, J.M.; Banker, G.A.; Clayton, D.F. Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. Brain Res. Dev. Brain Res. 1997, 99, 87–94. [Google Scholar] [CrossRef]
- Jensen, P.H.; Nielsen, M.S.; Jakes, R.; Dotti, C.G.; Goedert, M. Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson’s disease mutation. J. Biol. Chem. 1998, 273, 26292–26294. [Google Scholar] [CrossRef]
- Fortin, D.L.; Troyer, M.D.; Nakamura, K.; Kubo, S.; Anthony, M.D.; Edwards, R.H. Lipid rafts mediate the synaptic localization of alpha-synuclein. J. Neurosci. 2004, 24, 6715–6723. [Google Scholar] [CrossRef]
- Kahle, P.J.; Neumann, M.; Ozmen, L.; Muller, V.; Jacobsen, H.; Schindzielorz, A.; Okochi, M.; Leimer, U.; van Der Putten, H.; Probst, A.; et al. Subcellular localization of wild-type and Parkinson’s disease-associated mutant alpha -synuclein in human and transgenic mouse brain. J. Neurosci. 2000, 20, 6365–6373. [Google Scholar] [CrossRef]
- Lee, H.J.; Choi, C.; Lee, S.J. Membrane-bound alpha-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form. J. Biol. Chem. 2002, 277, 671–678. [Google Scholar] [CrossRef]
- Jakes, R.; Spillantini, M.G.; Goedert, M. Identification of two distinct synucleins from human brain. FEBS Lett. 1994, 345, 27–32. [Google Scholar] [CrossRef]
- Weinreb, P.H.; Zhen, W.; Poon, A.W.; Conway, K.A.; Lansbury, P.T., Jr. NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 1996, 35, 13709–13715. [Google Scholar] [CrossRef] [PubMed]
- Zhu, M.; Li, J.; Fink, A.L. The association of α-synuclein with membranes affects bilayer structure, stability, and fibril formation. J. Biol. Chem. 2003, 278, 40186–40197. [Google Scholar] [CrossRef]
- Zhang, Z.; Kang, S.S.; Liu, X.; Ahn, E.H.; Zhang, Z.; He, L.; Iuvone, P.M.; Duong, D.M.; Seyfried, N.T.; Benskey, M.J.; et al. Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson’s disease. Nat. Struct. Mol. Biol. 2017, 24, 632–642. [Google Scholar] [CrossRef]
- Gai, W.P.; Yuan, H.X.; Li, X.Q.; Power, J.T.; Blumbergs, P.C.; Jensen, P.H. In situ and in vitro study of colocalization and segregation of α-synuclein, ubiquitin, and lipids in Lewy bodies. Exp. Neurol. 2000, 166, 324–333. [Google Scholar] [CrossRef]
- Halliday, G.M.; Ophof, A.; Broe, M.; Jensen, P.H.; Kettle, E.; Fedorow, H.; Cartwright, M.I.; Griffiths, F.M.; Shepherd, C.E.; Double, K.L. α-synuclein redistributes to neuromelanin lipid in the substantia nigra early in Parkinson’s disease. Brain 2005, 128, 2654–2664. [Google Scholar] [CrossRef]
- Giasson, B.I.; Murray, I.V.; Trojanowski, J.Q.; Lee, V.M. A hydrophobic stretch of 12 amino acid residues in the middle of α-synuclein is essential for filament assembly. J. Biol. Chem. 2001, 276, 2380–2386. [Google Scholar] [CrossRef] [PubMed]
- Periquet, M.; Fulga, T.; Myllykangas, L.; Schlossmacher, M.G.; Feany, M.B. Aggregated α-synuclein mediates dopaminergic neurotoxicity in vivo. J. Neurosci. 2007, 27, 3338–3346. [Google Scholar] [CrossRef] [PubMed]
- Rodriguez, J.A.; Ivanova, M.I.; Sawaya, M.R.; Cascio, D.; Reyes, F.E.; Shi, D.; Sangwan, S.; Guenther, E.L.; Johnson, L.M.; Zhang, M.; et al. Structure of the toxic core of α-synuclein from invisible crystals. Nature 2015, 525, 486–490. [Google Scholar] [CrossRef] [PubMed]
- Bodles, A.M.; Guthrie, D.J.; Greer, B.; Irvine, G.B. Identification of the region of non-Aβ component (NAC) of Alzheimer’s disease amyloid responsible for its aggregation and toxicity. J. Neurochem. 2001, 78, 384–395. [Google Scholar] [CrossRef]
- Hong, D.P.; Xiong, W.; Chang, J.Y.; Jiang, C. The role of the C-terminus of human α-synuclein: Intra-disulfide bonds between the C-terminus and other regions stabilize non-fibrillar monomeric isomers. FEBS Lett. 2011, 585, 561–566. [Google Scholar] [CrossRef] [PubMed]
- Bertoncini, C.W.; Jung, Y.S.; Fernandez, C.O.; Hoyer, W.; Griesinger, C.; Jovin, T.M.; Zweckstetter, M. Release of long-range tertiary interactions potentiates aggregation of natively unstructured α-synuclein. Proc. Natl. Acad. Sci. USA 2005, 102, 1430–1435. [Google Scholar] [CrossRef] [PubMed]
- Calo, L.; Wegrzynowicz, M.; Santivanez-Perez, J.; Grazia Spillantini, M. Synaptic failure and alpha-synuclein. Mov. Disord. 2016, 31, 169–177. [Google Scholar] [CrossRef] [PubMed]
- Larsen, K.E.; Schmitz, Y.; Troyer, M.D.; Mosharov, E.; Dietrich, P.; Quazi, A.Z.; Savalle, M.; Nemani, V.; Chaudhry, F.A.; Edwards, R.H.; et al. Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis. J. Neurosci. 2006, 26, 11915–11922. [Google Scholar] [CrossRef] [PubMed]
- Nemani, V.M.; Lu, W.; Berge, V.; Nakamura, K.; Onoa, B.; Lee, M.K.; Chaudhry, F.A.; Nicoll, R.A.; Edwards, R.H. Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 2010, 65, 66–79. [Google Scholar] [CrossRef] [PubMed]
- Lundblad, M.; Decressac, M.; Mattsson, B.; Bjorklund, A. Impaired neurotransmission caused by overexpression of alpha-synuclein in nigral dopamine neurons. Proc. Natl. Acad. Sci. USA 2012, 109, 3213–3219. [Google Scholar] [CrossRef]
- Phan, J.A.; Stokholm, K.; Zareba-Paslawska, J.; Jakobsen, S.; Vang, K.; Gjedde, A.; Landau, A.M.; Romero-Ramos, M. Early synaptic dysfunction induced by alpha-synuclein in a rat model of Parkinson’s disease. Sci. Rep. 2017, 7, 6363. [Google Scholar] [CrossRef]
- Bussell, R., Jr.; Eliezer, D. Effects of Parkinson’s disease-linked mutations on the structure of lipid-associated alpha-synuclein. Biochemistry 2004, 43, 4810–4818. [Google Scholar] [CrossRef]
- Fredenburg, R.A.; Rospigliosi, C.; Meray, R.K.; Kessler, J.C.; Lashuel, H.A.; Eliezer, D.; Lansbury, P.T., Jr. The impact of the E46K mutation on the properties of alpha-synuclein in its monomeric and oligomeric states. Biochemistry 2007, 46, 7107–7118. [Google Scholar] [CrossRef] [PubMed]
- Burre, J.; Sharma, M.; Tsetsenis, T.; Buchman, V.; Etherton, M.R.; Sudhof, T.C. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 2010, 329, 1663–1667. [Google Scholar] [CrossRef] [PubMed]
- Diao, J.; Burre, J.; Vivona, S.; Cipriano, D.J.; Sharma, M.; Kyoung, M.; Sudhof, T.C.; Brunger, A.T. Native alpha-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2. Elife 2013, 2, e00592. [Google Scholar] [CrossRef] [PubMed]
- Logan, T.; Bendor, J.; Toupin, C.; Thorn, K.; Edwards, R.H. alpha-Synuclein promotes dilation of the exocytotic fusion pore. Nat. Neurosci. 2017, 20, 681–689. [Google Scholar] [CrossRef] [PubMed]
- Wang, C.; Zhang, K.; Cai, B.; Haller, J.E.; Carnazza, K.E.; Hu, J.; Zhao, C.; Tian, Z.; Hu, X.; Hall, D.; et al. VAMP2 chaperones α-synuclein in synaptic vesicle co-condensates. Nat. Cell Biol. 2024, 26, 1287–1295. [Google Scholar] [CrossRef]
- Davidson, W.S.; Jonas, A.; Clayton, D.F.; George, J.M. Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 1998, 273, 9443–9449. [Google Scholar] [CrossRef]
- Mori, A.; Hatano, T.; Inoshita, T.; Shiba-Fukushima, K.; Koinuma, T.; Meng, H.; Kubo, S.I.; Spratt, S.; Cui, C.; Yamashita, C.; et al. Parkinson’s disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and alpha-synuclein stability through membrane remodeling. Proc. Natl. Acad. Sci. USA 2019, 116, 20689–20699. [Google Scholar] [CrossRef] [PubMed]
- Perrin, R.J.; Woods, W.S.; Clayton, D.F.; George, J.M. Interaction of human alpha-Synuclein and Parkinson’s disease variants with phospholipids. Structural analysis using site-directed mutagenesis. J. Biol. Chem. 2000, 275, 34393–34398. [Google Scholar] [CrossRef]
- Rhoades, E.; Ramlall, T.F.; Webb, W.W.; Eliezer, D. Quantification of alpha-synuclein binding to lipid vesicles using fluorescence correlation spectroscopy. Biophys. J. 2006, 90, 4692–4700. [Google Scholar] [CrossRef]
- Galvagnion, C.; Brown, J.W.; Ouberai, M.M.; Flagmeier, P.; Vendruscolo, M.; Buell, A.K.; Sparr, E.; Dobson, C.M. Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of alpha-synuclein. Proc. Natl. Acad. Sci. USA 2016, 113, 7065–7070. [Google Scholar] [CrossRef] [PubMed]
- Kubo, S.; Nemani, V.M.; Chalkley, R.J.; Anthony, M.D.; Hattori, N.; Mizuno, Y.; Edwards, R.H.; Fortin, D.L. A combinatorial code for the interaction of alpha-synuclein with membranes. J. Biol. Chem. 2005, 280, 31664–31672. [Google Scholar] [CrossRef] [PubMed]
- Zakharova, I.O.; Sokolova, T.V.; Furaev, V.V.; Rychkova, M.P.; Avrova, N.F. Effects of oxidative stress inducers, neurotoxins, and ganglioside GM1 on Na+, K+-ATPase in PC12 and brain synaptosomes. Zhurnal Evoliutsionnoi Biokhimii Fiziol. 2007, 43, 148–154. [Google Scholar]
- Middleton, E.R.; Rhoades, E. Effects of curvature and composition on alpha-synuclein binding to lipid vesicles. Biophys. J. 2010, 99, 2279–2288. [Google Scholar] [CrossRef] [PubMed]
- van Meer, G.; Voelker, D.R.; Feigenson, G.W. Membrane lipids: Where they are and how they behave. Nat. Rev. Mol. Cell Biol. 2008, 9, 112–124. [Google Scholar] [CrossRef]
- Kobayashi, T.; Beuchat, M.H.; Chevallier, J.; Makino, A.; Mayran, N.; Escola, J.M.; Lebrand, C.; Cosson, P.; Kobayashi, T.; Gruenberg, J. Separation and characterization of late endosomal membrane domains. J. Biol. Chem. 2002, 277, 32157–32164. [Google Scholar] [CrossRef] [PubMed]
- O’Leary, E.I.; Jiang, Z.; Strub, M.P.; Lee, J.C. Effects of phosphatidylcholine membrane fluidity on theconformation and aggregation of N-terminally acetylated alpha-synuclein. J. Biol. Chem. 2018, 293, 11195–11205. [Google Scholar] [CrossRef]
- Chandra, S.; Chen, X.; Rizo, J.; Jahn, R.; Sudhof, T.C. A broken alpha -helix in folded alpha -Synuclein. J. Biol. Chem. 2003, 278, 15313–15318. [Google Scholar] [CrossRef] [PubMed]
- Drescher, M.; Veldhuis, G.; van Rooijen, B.D.; Milikisyants, S.; Subramaniam, V.; Huber, M. Antiparallel arrangement of the helices of vesicle-bound alpha-synuclein. J. Am. Chem. Soc. 2008, 130, 7796–7797. [Google Scholar] [CrossRef]
- Bodner, C.R.; Dobson, C.M.; Bax, A. Multiple tight phospholipid-binding modes of alpha-synuclein revealed by solution NMR spectroscopy. J. Mol. Biol. 2009, 390, 775–790. [Google Scholar] [CrossRef]
- Irwin, D.J.; Lee, V.M.; Trojanowski, J.Q. Parkinson’s disease dementia: Convergence of alpha-synuclein, tau and amyloid-beta pathologies. Nat. Rev. Neurosci. 2013, 14, 626–636. [Google Scholar] [CrossRef]
- Kordower, J.H.; Chu, Y.; Hauser, R.A.; Freeman, T.B.; Olanow, C.W. Lewybody-likepathologyinlong-term embryonic nigral transplants in Parkinson’s disease. Nat. Med. 2008, 14, 504–506. [Google Scholar] [CrossRef] [PubMed]
- Kordower, J.H.; Chu, Y.; Hauser, R.A.; Olanow, C.W.; Freeman, T.B. Transplanteddopaminergicneurons develop PD pathologic changes: A second case report. Mov. Disord. 2008, 23, 2303–2306. [Google Scholar] [CrossRef]
- Li, J.Y.; Englund, E.; Holton, J.L.; Soulet, D.; Hagell, P.; Lees, A.J.; Lashley, T.; Quinn, N.P.; Rehncrona, S.; Bjorklund, A.; et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat. Med. 2008, 14, 501–503. [Google Scholar] [CrossRef]
- Luk, K.C.; Song, C.; O’Brien, P.; Stieber, A.; Branch, J.R.; Brunden, K.R.; Trojanowski, J.Q.; Lee, V.M. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc. Natl. Acad. Sci. USA 2009, 106, 20051–20056. [Google Scholar] [CrossRef]
- Hansen, C.; Angot, E.; Bergstrom, A.L.; Steiner, J.A.; Pieri, L.; Paul, G.; Outeiro, T.F.; Melki, R.; Kallunki, P.; Fog, K.; et al. alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J. Clin. Investig. 2011, 121, 715–725. [Google Scholar] [CrossRef]
- Kordower, J.H.; Dodiya, H.B.; Kordower, A.M.; Terpstra, B.; Paumier, K.; Madhavan, L.; Sortwell, C.; Steece-Collier, K.; Collier, T.J. Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat. Neurobiol. Dis. 2011, 43, 552–557. [Google Scholar] [CrossRef] [PubMed]
- Luk, K.C.; Kehm, V.; Carroll, J.; Zhang, B.; O’Brien, P.; Trojanowski, J.Q.; Lee, V.M. Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 2012, 338, 949–953. [Google Scholar] [CrossRef] [PubMed]
- Shimozawa, A.; Ono, M.; Takahara, D.; Tarutani, A.; Imura, S.; Masuda-Suzukake, M.; Higuchi, M.; Yanai, K.; Hisanaga, S.I.; Hasegawa, M. Propagation of pathological alpha-synuclein in marmoset brain. Acta Neuropathol. Commun. 2017, 5, 12. [Google Scholar] [CrossRef]
- Okuzumi, A.; Kurosawa, M.; Hatano, T.; Takanashi, M.; Nojiri, S.; Fukuhara, T.; Yamanaka, T.; Miyazaki, H.; Yoshinaga, S.; Furukawa, Y.; et al. Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment. Acta Neuropathol. Commun. 2018, 6, 96. [Google Scholar] [CrossRef]
- Jo, E.; McLaurin, J.; Yip, C.M.; St George-Hyslop, P.; Fraser, P.E. alpha-Synuclein membrane interactions and lipid specificity. J. Biol. Chem. 2000, 275, 34328–34334. [Google Scholar] [CrossRef] [PubMed]
- Fares, M.B.; Ait-Bouziad, N.; Dikiy, I.; Mbefo, M.K.; Jovicic, A.; Kiely, A.; Holton, J.L.; Lee, S.J.; Gitler, A.D.; Eliezer, D.; et al. The novel Parkinson’s disease linked mutation G51D attenuates in vitro aggregation and membrane binding of alpha-synuclein, and enhances its secretion and nuclear localization in cells. Hum. Mol. Genet. 2014, 23, 4491–4509. [Google Scholar] [CrossRef] [PubMed]
- Bodner, C.R.; Maltsev, A.S.; Dobson, C.M.; Bax, A. Differential phospholipid binding of alpha-synuclein variants implicated in Parkinson’s disease revealed by solution NMR spectroscopy. Biochemistry 2010, 49, 862–871. [Google Scholar] [CrossRef] [PubMed]
- Khalaf, O.; Fauvet, B.; Oueslati, A.; Dikiy, I.; Mahul-Mellier, A.L.; Ruggeri, F.S.; Mbefo, M.K.; Vercruysse, F.; Dietler, G.; Lee, S.J.; et al. The H50Q mutation enhances alpha-synuclein aggregation, secretion, and toxicity. J. Biol. Chem. 2014, 289, 21856–21876. [Google Scholar] [CrossRef] [PubMed]
- Choi, W.; Zibaee, S.; Jakes, R.; Serpell, L.C.; Davletov, B.; Crowther, R.A.; Goedert, M. Mutation E46K increases phospholipid binding and assembly into filaments of human alpha-synuclein. FEBS Lett. 2004, 576, 363–368. [Google Scholar] [CrossRef] [PubMed]
- Conway, K.A.; Lee, S.J.; Rochet, J.C.; Ding, T.T.; Williamson, R.E.; Lansbury, P.T., Jr. Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: Implications for pathogenesis and therapy. Proc. Natl. Acad. Sci. USA 2000, 97, 571–576. [Google Scholar] [CrossRef] [PubMed]
- Ghosh, D.; Mondal, M.; Mohite, G.M.; Singh, P.K.; Ranjan, P.; Anoop, A.; Ghosh, S.; Jha, N.N.; Kumar, A.; Maji, S.K. The Parkinson’s disease-associated H50Q mutation accelerates α-Synuclein aggregation in vitro. Biochemistry 2013, 52, 6925–6927. [Google Scholar] [CrossRef]
- Shahmoradian, S.H.; Lewis, A.J.; Genoud, C.; Hench, J.; Moors, T.E.; Navarro, P.P.; Castano-Diez, D.; Schweighauser, G.; Graff-Meyer, A.; Goldie, K.N.; et al. Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nat. Neurosci. 2019, 22, 1099–1109. [Google Scholar] [CrossRef]
- Stöckl, M.T.; Zijlstra, N.; Subramaniam, V. α-Synuclein oligomers: An amyloid pore? Insights into mechanisms of α-synuclein oligomer-lipid interactions. Mol. Neurobiol. 2013, 47, 613–621. [Google Scholar] [CrossRef]
- Volles, M.J.; Lee, S.J.; Rochet, J.C.; Shtilerman, M.D.; Ding, T.T.; Kessler, J.C.; Lansbury, P.T., Jr. Vesicle permeabilization by protofibrillar alpha-synuclein: Implications for the pathogenesis and treatment of Parkinson’s disease. Biochemistry 2001, 40, 7812–7819. [Google Scholar] [CrossRef]
- Volles, M.J.; Lansbury, P.T., Jr. Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson’s disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 2002, 41, 4595–4602. [Google Scholar] [CrossRef] [PubMed]
- Stefanovic, A.N.; Lindhoud, S.; Semerdzhiev, S.A.; Claessens, M.M.; Subramaniam, V. Oligomers of Parkinson’s Disease-Related α-Synuclein Mutants Have Similar Structures but Distinctive Membrane Permeabilization Properties. Biochemistry 2015, 54, 3142–3150. [Google Scholar] [CrossRef]
- Uversky, V.N.; Li, J.; Fink, A.L. Metal-triggered structural transformations, aggregation, and fibrillation of human α-synuclein. A possible molecular NK between Parkinson’s disease and heavy metal exposure. J. Biol. Chem. 2001, 276, 44284–44296. [Google Scholar] [CrossRef] [PubMed]
- Kahle, P.J.; Neumann, M.; Ozmen, L.; Haass, C. Physiology and pathophysiology of alpha-synuclein. Cell culture and transgenic animal models based on a Parkinson’s disease-associated protein. Ann. N. Y. Acad. Sci. 2000, 920, 33–41. [Google Scholar] [CrossRef] [PubMed]
- Huebbe, P.; Rimbach, G. Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors. Ageing Res. Rev. 2017, 37, 146–161. [Google Scholar] [CrossRef] [PubMed]
- Varkey, J.; Isas, J.M.; Mizuno, N.; Jensen, M.B.; Bhatia, V.K.; Jao, C.C.; Petrlova, J.; Voss, J.C.; Stamou, D.G.; Steven, A.C.; et al. Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins. J. Biol. Chem. 2010, 285, 32486–32493. [Google Scholar] [CrossRef] [PubMed]
- Elliott, D.A.; Weickert, C.S.; Garner, B. Apolipoproteins in the brain: Implications for neurological and psychiatric disorders. Clin. Lipidol. 2010, 51, 555–573. [Google Scholar] [CrossRef] [PubMed]
- Tamam, Y.; Tasdemir, N.; Yalman, M.; Tamam, B. Association of apolipoprotein E genotypes with prognosis in multiple sclerosis. Eur. Rev. Med. Pharmacol. Sci. 2011, 15, 1122–1130. [Google Scholar] [PubMed]
- Ponsford, J.; McLaren, A.; Schönberger, M.; Burke, R.; Rudzki, D.; Olver, J.; Ponsford, M. The association between apolipoprotein E and traumatic brain injury severity and functional outcome in a rehabilitation sample. J. Neurotrauma 2011, 28, 1683–1692. [Google Scholar] [CrossRef]
- Amouyel, P.; Vidal, O.; Launay, J.M.; Laplanche, J.L. The apolipoprotein E alleles as major susceptibility factors for Creutzfeldt-Jakob disease. The French Research Group on Epidemiology of Human Spongiform Encephalopathies. Lancet 1994, 344, 1315–1318. [Google Scholar] [CrossRef]
- Wilhelmus, M.M.; Bol, J.G.; Van Haastert, E.S.; Rozemuller, A.J.; Bu, G.; Drukarch, B.; Hoozemans, J.J. Apolipoprotein E and LRP1 increase early in Parkinson’s disease pathogenesis. Am. J. Pathol. 2011, 179, 2152–2156. [Google Scholar] [CrossRef] [PubMed]
- Emamzadeh, F.N.; Aojula, H.; McHugh, P.C.; Allsop, D. Effects of different isoforms of apoE on aggregation of the α-synuclein protein implicated in Parkinson’s disease. Neurosci. Lett. 2016, 618, 146–151. [Google Scholar] [CrossRef] [PubMed]
- Paslawski, W.; Zareba-Paslawska, J.; Zhang, X.; Hölzl, K.; Wadensten, H.; Shariatgorji, M.; Janelidze, S.; Hansson, O.; Forsgren, L.; Andrén, P.E.; et al. α-synuclein-lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson’s disease patients. Proc. Natl. Acad. Sci. USA 2019, 116, 15226–15235. [Google Scholar] [CrossRef] [PubMed]
- Brangwynne, C.P.; Eckmann, C.R.; Courson, D.S.; Rybarska, A.; Hoege, C.; Gharakhani, J.; Jülicher, F.; Hyman, A.A. Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 2009, 324, 1729–1732. [Google Scholar] [CrossRef]
- Hyman, A.A.; Weber, C.A.; Jülicher, F. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 2014, 30, 39–58. [Google Scholar] [CrossRef] [PubMed]
- Banani, S.F.; Rice, A.M.; Peeples, W.B.; Lin, Y.; Jain, S.; Parker, R.; Rosen, M.K. Compositional control of phase-separated cellular bodies. Cell 2016, 166, 651–663. [Google Scholar] [CrossRef] [PubMed]
- Shin, Y.; Brangwynne, C.P. Liquid phase condensation in cell physiology and disease. Science 2017, 357, eaaf4382. [Google Scholar] [CrossRef] [PubMed]
- Alberti, S. Phase separation in biology. Curr. Biol. 2017, 27, R1097–R1102. [Google Scholar] [CrossRef]
- Boeynaems, S.; Alberti, S.; Fawzi, N.L.; Mittag, T.; Polymenidou, M.; Rousseau, F.; Schymkowitz, J.; Shorter, J.; Wolozin, B.; Van Den Bosch, L.; et al. Protein phase separation: A new phase in cell biology. Trends Cell Biol. 2018, 28, 420–435. [Google Scholar] [CrossRef]
- Holehouse, A.S.; Pappu, R.V. Functional Implications of Intracellular Phase Transitions. Biochemistry 2018, 57, 2415–2423. [Google Scholar] [CrossRef]
- Patel, A.; Lee, H.O.; Jawerth, L.; Maharana, S.; Jahnel, M.; Hein, M.Y.; Stoynov, S.; Mahamid, J.; Saha, S.; Franzmann, T.M.; et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 2015, 162, 1066–1077. [Google Scholar] [CrossRef]
- Conicella, A.E.; Zerze, G.H.; Mittal, J.; Fawzi, N.L. ALS mutations disrupt phase separation mediated by α-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 2016, 24, 1537–1549. [Google Scholar] [CrossRef]
- Wegmann, S.; Eftekharzadeh, B.; Tepper, K.; Zoltowska, K.M.; Bennett, R.E.; Dujardin, S.; Laskowski, P.R.; MacKenzie, D.; Kamath, T.; Commins, C.; et al. Tau protein liquid-liquid phase separation can initiate tau aggregation. EMBO J. 2018, 37, e98049. [Google Scholar] [CrossRef]
- Ambadipudi, S.; Biernat, J.; Riedel, D.; Mandelkow, E.; Zweckstetter, M. Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. Nat. Commun. 2017, 8, 275. [Google Scholar] [CrossRef]
- Molliex, A.; Temirov, J.; Lee, J.; Coughlin, M.; Kanagaraj, A.P.; Kim, H.J.; Mittag, T.; Taylor, J.P. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 2015, 163, 123–133. [Google Scholar] [CrossRef]
- Ray, S.; Singh, N.; Kumar, R.; Patel, K.; Pandey, S.; Datta, D.; Mahato, J.; Panigrahi, R.; Navalkar, A.; Mehra, S.; et al. α-Synuclein aggregation nucleates through liquid-liquid phase separation. Nat. Chem. 2020, 12, 705–716. [Google Scholar] [CrossRef]
- Huang, S.; Xu, B.; Liu, Y. Calcium promotes α-synuclein liquid-liquid phase separation to accelerate amyloid aggregation. Biochem. Biophys. Res. Commun. 2022, 603, 13–20. [Google Scholar] [CrossRef]
- Van Maarschalkerweerd, A.; Vetri, V.; Langkilde, A.E.; Foderà, V.; Vestergaard, B. Protein/lipid coaggregates are formed during α-synuclein-induced disruption of lipid bilayers. Biomacromolecules 2014, 15, 3643–3654. [Google Scholar] [CrossRef] [PubMed]
- Roy, S.; Wolman, L. Ultrastructural observations in Parkinsonism. J. Pathol. 1969, 99, 39–44. [Google Scholar] [CrossRef] [PubMed]
- Kosaka, K.; Oyanagi, S.; Matsushita, M.; Hori, A. Presenile dementia with Alzheimer-, Pick- and Lewy-body changes. Acta Neuropathol. 1976, 36, 221–233. [Google Scholar] [CrossRef] [PubMed]
- Trojanowski, J.Q.; Lee, V.M. Aggregation of neurofilament and alpha-synuclein proteins in Lewy bodies: Implications for the pathogenesis of Parkinson disease and Lewy body dementia. Arch. Neurol. 1998, 55, 151–152. [Google Scholar] [CrossRef]
- Jensen, P.H.; Islam, K.; Kenney, J.; Nielsen, M.S.; Power, J.; Gai, W.P. Microtubule-associated protein 1B is a component of cortical Lewy bodies and binds alpha-synuclein filaments. J. Biol. Chem. 2000, 275, 21500–21507. [Google Scholar] [CrossRef] [PubMed]
- Flavin, W.P.; Bousset, L.; Green, Z.C.; Chu, Y.; Skarpathiotis, S.; Chaney, M.J.; Kordower, J.H.; Melki, R.; Campbell, E.M. Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins. Acta Neuropathol. 2017, 134, 629–653. [Google Scholar] [CrossRef] [PubMed]
- den Jager, W.A. Sphingomyelin in Lewy inclusion bodies in Parkinson’s disease. Arch. Neurol. 1969, 21, 615–619. [Google Scholar] [CrossRef] [PubMed]
- Issidorides, M.R.; Mytilineou, C.; Panayotacopoulou, M.T.; Yahr, M.D. Lewy bodies in parkinsonism share components with intraneuronal protein bodies of normal brains. J. Neural. Transm. Park. Dis. Dement. Sect. 1991, 3, 49–61. [Google Scholar] [CrossRef] [PubMed]
- Sidransky, E.; Nalls, M.A.; Aasly, J.O.; Aharon-Peretz, J.; Annesi, G.; Barbosa, E.R.; Bar-Shira, A.; Berg, D.; Bras, J.; Brice, A.; et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N. Engl. J. Med. 2009, 361, 1651–1661. [Google Scholar] [CrossRef] [PubMed]
- Migdalska-Richards, A.; Schapira, A.H. The relationship between glucocerebrosidase mutations and Parkinson disease. J. Neurochem. 2016, 139, 77–90. [Google Scholar] [CrossRef] [PubMed]
- Mizuno, H.; Fujikake, N.; Wada, K.; Nagai, Y. α-Synuclein transgenic Drosophila as a model of Parkinson’s disease and related synucleinopathies. Park. Dis. 2010, 2011, 212706. [Google Scholar] [CrossRef]
- Zunke, F.; Moise, A.C.; Belur, N.R.; Gelyana, E.; Stojkovska, I.; Dzaferbegovic, H.; Toker, N.J.; Jeon, S.; Fredriksen, K.; Mazzulli, J.R. Reversible conformational conversion of α-synuclein into toxic assemblies by glucosylceramide. Neuron 2018, 97, 92–107. [Google Scholar] [CrossRef]
- Shachar, T.; Lo Bianco, C.; Recchia, A.; Wiessner, C.; Raas-Rothschild, A.; Futerman, A.H. Lysosomal storage disorders and Parkinson’s disease: Gaucher disease and beyond. Mov. Disord. 2011, 26, 1593–1604. [Google Scholar] [CrossRef]
- Walkley, S.U. Secondary accumulation of gangliosides in lysosomal storage disorders. Semin. Cell Dev. Biol. 2004, 15, 433–444. [Google Scholar] [CrossRef] [PubMed]
- Gegg, M.E.; Burke, D.; Heales, S.J.; Cooper, J.M.; Hardy, J.; Wood, N.W.; Schapira, A.H.V. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann. Neurol. 2012, 72, 455–463. [Google Scholar] [CrossRef] [PubMed]
- Moors, T.E.; Paciotti, S.; Ingrassia, A.; Quadri, M.; Breedveld, G.; Tasegian, A.; Chiasserini, D.; Eusebi, P.; Duran-Pacheco, G.; Kremer, T.; et al. Characterization of brain lysosomal activities in GBA-related and sporadic Parkinson’s disease and dementia with Lewy bodies. Mol. Neurobiol. 2018, 56, 1344–1355. [Google Scholar] [CrossRef]
- Murphy, K.E.; Gysbers, A.M.; Abbott, S.K.; Tayebi, N.; Kim, W.S.; Sidransky, E.; Cooper, A.; Garner, B.; Halliday, G.M. Reduced glucocerebrosidase is associated with increased alpha- synuclein in sporadic Parkinson’s disease. Brain 2014, 137, 834–848. [Google Scholar] [CrossRef]
- Chiasserini, D.; Paciotti, S.; Eusebi, P.; Persichetti, E.; Tasegian, A.; Kurzawa-Akanbi, M.; Chinnery, P.F.; Morris, C.M.; Calabresi, P.; Parnetti, L.; et al. Selective loss of glucocerebrosidase activity in sporadic Parkinson’s disease and dementia with Lewy bodies. Mol. Neurodegener. 2015, 10, 15. [Google Scholar] [CrossRef]
- Quadri, M.; Fang, M.; Picillo, M.; Olgiati, S.; Breedveld, G.J.; Graafland, J.; Wu, B.; Xu, F.; Erro, R.; Amboni, M.; et al. Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. Hum. Mutat. 2013, 34, 1208–1215. [Google Scholar] [CrossRef] [PubMed]
- Sumi-Akamaru, H.; Beck, G.; Shinzawa, K.; Kato, S.; Riku, Y.; Yoshida, M.; Fujimura, H.; Tsujimoto, Y.; Sakoda, S.; Mochizuki, H. High expression of α-synuclein in damaged mitochondria with PLA2G6 dysfunction. Acta Neuropathol. Commun. 2016, 4, 27. [Google Scholar] [CrossRef] [PubMed]
- Lin, G.; Lee, P.T.; Chen, K.; Mao, D.; Tan, K.L.; Zuo, Z.; Lin, W.W.; Wang, L.; Bellen, H.J. Phospholipase PLA2G6, a Parkinsonism-Associated Gene, Affects Vps26 and Vps35, Retromer Function, and Ceramide Levels, Similar to α-Synuclein Gain. Cell Metab. 2018, 28, 605–618. [Google Scholar] [CrossRef] [PubMed]
- Olsen, A.L.; Feany, M.B. Parkinson’s disease risk genes act in glia to control neuronal α-synuclein toxicity. Neurobiol. Dis. 2021, 159, 105482. [Google Scholar] [CrossRef]
- Hatton, C.; Ghanem, S.S.; Koss, D.J.; Abdi, I.Y.; Gibbons, E.; Guerreiro, R.; Bras, J.; International DLB Genetics Consortium; Walker, L.; Gelpi, E.; et al. Prion-like α-synuclein pathology in the brain of infants with Krabbe disease. Brain 2022, 145, 1257–1263. [Google Scholar] [CrossRef]
- Suzuki, K.; Iseki, E.; Togo, T.; Yamaguchi, A.; Katsuse, O.; Katsuyama, K.; Hirayasu, Y. Neuronal and glial accumulation of a- and b-synucleins in human lipidoses. Acta Neuropathol. 2007, 114, 481–489. [Google Scholar] [CrossRef]
- Hamano, K.; Hayashi, M.; Shioda, K.; Fukatsu, R.; Mizutani, S. Mechanisms of neurodegeneration in mucopolysaccharidoses II and IIIB: Analysis of human brain tissue. Acta Neuropathol. 2008, 115, 547–559. [Google Scholar] [CrossRef] [PubMed]
- Martinez, Z.; Zhu, M.; Han, S.; Fink, A.L. GM1 specifically interacts with alpha-synuclein and inhibits fibrillation. Biochemistry 2007, 46, 1868–1877. [Google Scholar] [CrossRef] [PubMed]
- Fantini, J.; Yahi, N. Molecular basis for the glycosphingolipid-binding specificity of a-synuclein: Key role of tyrosine 39 in membrane insertion. J. Mol. Biol. 2011, 408, 654–669. [Google Scholar] [CrossRef] [PubMed]
- Grey, M.; Dunning, C.J.; Gaspar, R.; Grey, C.; Brundin, P.; Sparr, E.; Linse, S. Acceleration of a-synuclein aggregation by exosomes. J. Biol. Chem. 2015, 290, 2969–2982. [Google Scholar] [CrossRef]
- De Franceschi, G.; Frare, E.; Bubacco, L.; Mammi, S.; Fontana, A.; Polverino de Laureto, P. Molecular insights into the interaction between α-synuclein and docosahexaenoic acid. J. Mol. Biol. 2009, 394, 94–107. [Google Scholar] [CrossRef]
- Sharon, R.; Goldberg, M.S.; Bar-Josef, I.; Betensky, R.A.; Shen, J.; Selkoe, D.J. α-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 2001, 98, 9110–9115. [Google Scholar] [CrossRef]
- Lücke, C.; Gantz, D.L.; Klimtchuk, E.; Hamilton, J.A. Interactions between fatty acids and α-synuclein. J. Lipid Res. 2006, 47, 1714–1724. [Google Scholar] [CrossRef]
- 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 2006, 45, 15610–15616. [Google Scholar] [CrossRef]
- De Franceschi, G.; Polverino de Laureto, P. Role of different regions of α-synuclein in the interaction with the brain fatty acid DHA. J. Chromatogr. Sep. Tech. 2014, 5, 219–226. [Google Scholar] [CrossRef]
- Sharon, R.; Bar-Joseph, I.; Frosch, M.P.; Walsh, D.M.; Hamilton, J.A.; Selkoe, D.J. The formation of highly soluble oligomers of α-synuclein is regulated by fatty acids and enhanced in Parkinson’s disease. Neuron 2003, 37, 583–595. [Google Scholar] [CrossRef]
- De Franceschi, G.; Frare, E.; Pivato, M.; Relini, A.; Penco, A.; Greggio, E.; Bubacco, L.; Fontana, A.; Polverino de Laureto, P. Structural and morphological characterization of aggregated species of α-synuclein induced by docosahexaenoic acid. J. Biol. Chem. 2011, 286, 22262–22274. [Google Scholar] [CrossRef] [PubMed]
- Necula, M.; Chirita, C.N.; Kuret, J. Rapid anionic micelle-mediated α-synuclein fibrillization in vitro. J. Biol. Chem. 2003, 278, 46674–46680. [Google Scholar] [CrossRef]
- Iljina, M.; Tosatto, L.; Choi, M.L.; Sang, J.C.; Ye, Y.; Hughes, C.D.; Bryant, C.E.; Gandhi, S.; Klenerman, D. Arachidonic acid mediates the formation of abundant α-helical multimers of α-synuclein. Sci. Rep. 2016, 6, 33928. [Google Scholar] [CrossRef]
- 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. 2001, 276, 41958–41962. [Google Scholar] [CrossRef] [PubMed]
- Riedel, M.; Goldbaum, O.; Wille, M.; Richter-Landsberg, C. Membrane lipid modification by docosahexaenoic acid (DHA) promotes the formation of α-synuclein inclusion bodies immunopositive for SUMO-1 in oligodendroglial cells after oxidative stress. J. Mol. Neurosci. 2011, 43, 290–302. [Google Scholar] [CrossRef] [PubMed]
- Almandoz-Gil, L.; Welander, H.; Ihse, E.; Khoonsari, P.E.; Musunuri, S.; Lendel, C.; Sigvardson, J.; Karlsson, M.; Ingelsson, M.; Kultima, K.; et al. Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways. Free Radic. Biol. Med. 2017, 110, 421–431. [Google Scholar] [CrossRef]
αSyn Mutations | Lipid-Binding Affinity | Aggregation |
---|---|---|
A30P | ↓ | ↓ |
E46K | ↑ | ↑ |
H50Q | ≈ | ↑ |
G51D | ↓ | ↓ |
A53T | ≈ | ↑ |
A53E | ↓ |
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Kamano, S.; Ozawa, D.; Ikenaka, K.; Nagai, Y. Role of Lipids in the Pathogenesis of Parkinson’s Disease. Int. J. Mol. Sci. 2024, 25, 8935. https://doi.org/10.3390/ijms25168935
Kamano S, Ozawa D, Ikenaka K, Nagai Y. Role of Lipids in the Pathogenesis of Parkinson’s Disease. International Journal of Molecular Sciences. 2024; 25(16):8935. https://doi.org/10.3390/ijms25168935
Chicago/Turabian StyleKamano, Shumpei, Daisaku Ozawa, Kensuke Ikenaka, and Yoshitaka Nagai. 2024. "Role of Lipids in the Pathogenesis of Parkinson’s Disease" International Journal of Molecular Sciences 25, no. 16: 8935. https://doi.org/10.3390/ijms25168935