Examining the Toxicity of α-Synuclein in Neurodegenerative Disorders
Abstract
:Simple Summary
Abstract
1. Introduction
2. Properties, Functions, and History of α-Synuclein
3. Post-translational Modifications of α-Synuclein in PD
3.1. Phosphorylation
3.2. Nitration
3.3. Dopamine Modification
3.4. Sumoylation, O-GlcNAcylation, Ubiquitination, and Truncation
4. Conformations of α-Synuclein
5. Pathways Implicated in α-Synuclein Toxicity
6. Examining the Interplay of α-Synuclein with Tau and Aβ
7. Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
- Gitler, A.D.; Dhillon, P.; Shorter, J. Neurodegenerative disease: Models, mechanisms, and a new hope. Dis. Model. Mech. 2017, 10, 499–502. [Google Scholar] [CrossRef] [Green Version]
- Dorsey, E.R.; Elbaz, A.; Nichols, E.; Abd-Allah, F.; Abdelalim, A.; Adsuar, J.C.; Ansha, G.M.; Brayne, C.; Choi, J.Y.; Collado-Mateo, D.; et al. Global, regional, and national burden of Parkinson’s disease, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018, 17, 939–953. [Google Scholar] [CrossRef] [Green Version]
- Balestrino, R.; Schapira, A.H.V. Parkinson disease. Eur. J. Neurol. 2020, 27, 27–42. [Google Scholar] [CrossRef] [PubMed]
- Váradi, C. Clinical Features of Parkinson’s Disease: The Evolution of Critical Symptoms. Biology 2020, 9, 103. [Google Scholar] [CrossRef] [PubMed]
- Conway, K.A.; Rochet, J.C.; Bieganski, R.M.; Lansbury, P.T. Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science 2001, 294, 1346–1349. [Google Scholar] [CrossRef] [PubMed]
- Spillantini, M.G.; Crowther, R.A.; Jakes, R.; Hasegawa, M.; Goedert, M. Alpha-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] [Green Version]
- Polymeropoulos, M.H.; Lavedan, C.; Leroy, E.; Ide, S.E.; Dehejia, A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer, R.; et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997, 276, 2045–2047. [Google Scholar] [CrossRef] [Green Version]
- Wong, Y.C.; Krainc, D. α-synuclein toxicity in neurodegeneration: Mechanism and therapeutic strategies. Nat. Med. 2017, 23, 1–13. [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. alpha-Synuclein locus triplication causes Parkinson’s disease. Science 2003, 302, 841. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chartier-Harlin, M.C.; Kachergus, J.; Roumier, C.; Mouroux, V.; Douay, X.; Lincoln, S.; Levecque, C.; Larvor, L.; Andrieux, J.; Hulihan, M.; et al. Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 2004, 364, 1167–1169. [Google Scholar] [CrossRef]
- Zhang, J.; Li, X.; Li, J.D. The Roles of Post-translational Modifications on α-Synuclein in the Pathogenesis of Parkinson’s Diseases. Front Neurosci. 2019, 13, 381. [Google Scholar] [CrossRef] [Green Version]
- 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] [Green Version]
- 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] [Green Version]
- Maroteaux, L.; Scheller, R.H. The rat brain synucleins; family of proteins transiently associated with neuronal membrane. Brain Res. Mol. Brain Res. 1991, 11, 335–343. [Google Scholar] [CrossRef]
- Bendor, J.T.; Logan, T.P.; Edwards, R.H. The function of α-synuclein. Neuron 2013, 79, 1044–1066. [Google Scholar] [CrossRef] [Green Version]
- Dikiy, I.; Eliezer, D. Folding and misfolding of alpha-synuclein on membranes. Biochim. Biophys. Acta 2012, 1818, 1013–1018. [Google Scholar] [CrossRef] [Green Version]
- Prusiner, S.B.; Woerman, A.L.; Mordes, D.A.; Watts, J.C.; Rampersaud, R.; Berry, D.B.; Patel, S.; Oehler, A.; Lowe, J.K.; Kravitz, S.N.; et al. Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc. Natl. Acad. Sci. USA 2015, 112, E5308–E5317. [Google Scholar] [CrossRef] [Green Version]
- Woerman, A.L.; Stöhr, J.; Aoyagi, A.; Rampersaud, R.; Krejciova, Z.; Watts, J.C.; Ohyama, T.; Patel, S.; Widjaja, K.; Oehler, A.; et al. Propagation of prions causing synucleinopathies in cultured cells. Proc. Natl. Acad. Sci. USA 2015, 112, E4949–E4958. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Scott, D.; Roy, S. α-Synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis. J. Neurosci. 2012, 32, 10129–10135. [Google Scholar] [CrossRef] [Green Version]
- Burré, J.; Sharma, M.; Südhof, T.C. α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc. Natl. Acad. Sci. USA 2014, 111, E4274–E4283. [Google Scholar] [CrossRef] [Green Version]
- 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] [Green Version]
- Alerte, T.N.; Akinfolarin, A.A.; Friedrich, E.E.; Mader, S.A.; Hong, C.S.; Perez, R.G. Alpha-synuclein aggregation alters tyrosine hydroxylase phosphorylation and immunoreactivity: Lessons from viral transduction of knockout mice. Neurosci. Lett. 2008, 435, 24–29. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gorbatyuk, O.S.; Li, S.; Nguyen, F.N.; Manfredsson, F.P.; Kondrikova, G.; Sullivan, L.F.; Meyers, C.; Chen, W.; Mandel, R.J.; Muzyczka, N. α-Synuclein expression in rat substantia nigra suppresses phospholipase D2 toxicity and nigral neurodegeneration. Mol. Ther. 2010, 18, 1758–1768. [Google Scholar] [CrossRef] [PubMed]
- McDermott, M.; Wakelam, M.J.; Morris, A.J. Phospholipase D. Biochem. Cell Biol. 2004, 82, 225–253. [Google Scholar]
- Rappley, I.; Gitler, A.D.; Selvy, P.E.; LaVoie, M.J.; Levy, B.D.; Brown, H.A.; Lindquist, S.; Selkoe, D.J. Evidence that alpha-synuclein does not inhibit phospholipase D. Biochemistry 2009, 48, 1077–1083. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Emmanouilidou, E.; Melachroinou, K.; Roumeliotis, T.; Garbis, S.D.; Ntzouni, M.; Margaritis, L.H.; Stefanis, L.; Vekrellis, K. Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J. Neurosci. 2010, 30, 6838–6851. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- El-Agnaf, O.M.; Salem, S.A.; Paleologou, K.E.; Cooper, L.J.; Fullwood, N.J.; Gibson, M.J.; Curran, M.D.; Court, J.A.; Mann, D.M.; Ikeda, S.; et al. Alpha-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB J. 2003, 17, 1945–1947. [Google Scholar] [CrossRef]
- El-Agnaf, O.M.; Salem, S.A.; Paleologou, K.E.; Curran, M.D.; Gibson, M.J.; Court, J.A.; Schlossmacher, M.G.; Allsop, D. Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. FASEB J. 2006, 20, 419–425. [Google Scholar] [CrossRef]
- Emmanouilidou, E.; Elenis, D.; Papasilekas, T.; Stranjalis, G.; Gerozissis, K.; Ioannou, P.C.; Vekrellis, K. Assessment of α-synuclein secretion in mouse and human brain parenchyma. PLoS ONE 2011, 6, e22225. [Google Scholar] [CrossRef]
- Lee, H.J.; Patel, S.; Lee, S.J. Intravesicular localization and exocytosis of alpha-synuclein and its aggregates. J. Neurosci. 2005, 25, 6016–6024. [Google Scholar] [CrossRef]
- Sung, J.Y.; Park, S.M.; Lee, C.H.; Um, J.W.; Lee, H.J.; Kim, J.; Oh, Y.J.; Lee, S.T.; Paik, S.R.; Chung, K.C. Proteolytic cleavage of extracellular secreted {alpha}-synuclein via matrix metalloproteinases. J. Biol. Chem. 2005, 280, 25216–25224. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Van Niel, G.; Porto-Carreiro, I.; Simoes, S.; Raposo, G. Exosomes: A common pathway for a specialized function. J. Biochem. 2006, 140, 13–21. [Google Scholar] [CrossRef] [PubMed]
- Vincent, J.P.; Magee, T. Argosomes: Membrane fragments on the run. Trends Cell Biol. 2002, 12, 57–60. [Google Scholar] [CrossRef]
- Théry, C.; Zitvogel, L.; Amigorena, S. Exosomes: Composition, biogenesis and function. Nat. Rev. Immunol. 2002, 2, 569–579. [Google Scholar] [CrossRef]
- Mehul, B.; Hughes, R.C. Plasma membrane targetting, vesicular budding and release of galectin 3 from the cytoplasm of mammalian cells during secretion. J. Cell Sci. 1997, 110, 1169–1178. [Google Scholar] [CrossRef]
- Hughes, R.C. Secretion of the galectin family of mammalian carbohydrate–binding proteins. Biochim. Biophys. Acta 1999, 1473, 172–185. [Google Scholar] [CrossRef]
- Krüger, R.; Kuhn, W.; Müller, T.; Woitalla, D.; Graeber, M.; Kösel, S.; Przuntek, H.; Epplen, J.T.; Schöls, L.; Riess, O. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat. Genet. 1998, 18, 106–108. [Google Scholar] [CrossRef]
- Iacono, D.; Geraci-Erck, M.; Rabin, M.L.; Adler, C.H.; Serrano, G.; Beach, T.G.; Kurlan, R. Parkinson disease and incidental Lewy body disease: Just a question of time? Neurology 2015, 85, 1670–1679. [Google Scholar] [CrossRef] [Green Version]
- Fagerqvist, T.; Lindström, V.; Nordström, E.; Lord, A.; Tucker, S.M.; Su, X.; Sahlin, C.; Kasrayan, A.; Andersson, J.; Welander, H.; et al. Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation. J. Neurochem. 2013, 126, 131–144. [Google Scholar] [CrossRef]
- Gómez-Benito, M.; Granado, N.; García-Sanz, P.; Michel, A.; Dumoulin, M.; Moratalla, R. Modeling Parkinson’s Disease With the Alpha-Synuclein Protein. Front. Pharmacol. 2020, 11, 356. [Google Scholar] [CrossRef]
- Fujiwara, H.; Hasegawa, M.; Dohmae, N.; Kawashima, A.; Masliah, E.; Goldberg, M.S.; Shen, J.; Takio, K.; Iwatsubo, T. Alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell. Biol. 2002, 4, 160–164. [Google Scholar] [CrossRef]
- Muntané, G.; Ferrer, I.; Martinez-Vicente, M. α-synuclein phosphorylation and truncation are normal events in the adult human brain. Neuroscience 2012, 200, 106–119. [Google Scholar] [CrossRef]
- Oueslati, A. Implication of Alpha-Synuclein Phosphorylation at S129 in Synucleinopathies: What Have We Learned in the Last Decade? J. Parkinsons Dis. 2016, 6, 39–51. [Google Scholar] [CrossRef] [Green Version]
- Barrett, P.J.; Timothy, G.J. Post-translational modification of α-synuclein in Parkinson’s disease. Brain Res. 2015, 1628, 247–253. [Google Scholar] [CrossRef]
- Schell, H.; Hasegawa, T.; Neumann, M.; Kahle, P.J. Nuclear and neuritic distribution of serine-129 phosphorylated alpha-synuclein in transgenic mice. Neuroscience 2009, 160, 796–804. [Google Scholar] [CrossRef] [PubMed]
- Sato, H.; Kato, T.; Arawaka, S. The role of Ser129 phosphorylation of α-synuclein in neurodegeneration of Parkinson’s disease: A review of in vivo models. Rev. Neurosci. 2013, 24, 115–123. [Google Scholar] [CrossRef] [PubMed]
- Smith, W.W.; Margolis, R.L.; Li, X.; Troncoso, J.C.; Lee, M.K.; Dawson, V.L.; Dawson, T.M.; Iwatsubo, T.; Ross, C.A. Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells. J. Neurosci. 2005, 25, 5544–5552. [Google Scholar] [CrossRef] [PubMed]
- Mbefo, M.K.; Paleologou, K.E.; Boucharaba, A.; Oueslati, A.; Schell, H.; Fournier, M.; Olschewski, D.; Yin, G.; Zweckstetter, M.; Masliah, E.; et al. Phosphorylation of synucleins by members of the Polo-like kinase family. J. Biol. Chem. 2010, 285, 2807–2822. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Azeredo da Silveira, S.; Schneider, B.L.; Cifuentes-Diaz, C.; Sage, D.; Abbas-Terki, T.; Iwatsubo, T.; Unser, M.; Aebischer, P. Phosphorylation does not prompt, nor prevent, the formation of alpha-synuclein toxic species in a rat model of Parkinson’s disease. Hum. Mol. Genet. 2009, 18, 872–887. [Google Scholar]
- Chen, L.; Feany, M.B. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat. Neurosci. 2005, 8, 657–663. [Google Scholar] [CrossRef]
- Chen, L.; Periquet, M.; Wang, X.; Negro, A.; McLean, P.J.; Hyman, B.T.; Feany, M.B. Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. J. Clin. Investig. 2009, 119, 3257–3265. [Google Scholar] [PubMed] [Green Version]
- Luth, E.S.; Stavrovskaya, I.G.; Bartels, T.; Kristal, B.S.; Selkoe, D.J. Soluble, prefibrillar α-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. J. Biol. Chem. 2014, 289, 21490–21507. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Robin, M.A.; Prabu, S.K.; Raza, H.; Anandatheerthavarada, H.K.; Avadhani, N.G. Phosphorylation enhances mitochondrial targeting of GSTA4-4 through increased affinity for binding to cytoplasmic Hsp70. J. Biol. Chem. 2003, 278, 18960–18970. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Linseman, D.A.; Butts, B.D.; Precht, T.A.; Phelps, R.A.; Le, S.S.; Laessig, T.A.; Bouchard, R.J.; Florez-McClure, M.L.; Heidenreich, K.A. Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J. Neurosci. 2004, 24, 9993–10002. [Google Scholar] [CrossRef] [PubMed]
- Moreira, P.I.; Sayre, L.M.; Zhu, X.; Nunomura, A.; Smith, M.A.; Perry, G. Detection and localization of markers of oxidative stress by in situ methods: Application in the study of Alzheimer disease. Methods Mol. Biol. 2010, 610, 419–434. [Google Scholar] [PubMed] [Green Version]
- Perfeito, R.; Lázaro, D.F.; Outeiro, T.F.; Rego, A.C. Linking alpha-synuclein phosphorylation to reactive oxygen species formation and mitochondrial dysfunction in SH-SY5Y cells. Mol. Cell. Neurosci. 2014, 62, 51–59. [Google Scholar] [CrossRef] [PubMed]
- Good, P.F.; Hsu, A.; Werner, P.; Perl, D.P.; Olanow, C.W. Protein nitration in Parkinson’s disease. J. Neuropathol Exp. Neurol. 1998, 57, 338–342. [Google Scholar] [CrossRef] [PubMed]
- Giasson, B.I.; Duda, J.E.; Murray, I.V.; Chen, Q.; Souza, J.M.; Hurtig, H.I.; Ischiropoulos, H.; Trojanowski, J.Q.; Lee, V.M. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 2000, 290, 985–989. [Google Scholar] [CrossRef] [PubMed]
- Al-Hilaly, Y.K.; Biasetti, L.; Blakeman, B.J.; Pollack, S.J.; Zibaee, S.; Abdul-Sada, A.; Thorpe, J.R.; Xue, W.F.; Serpell, L.C. The involvement of dityrosine crosslinking in α-synuclein assembly and deposition in Lewy Bodies in Parkinson’s disease. Sci. Rep. 2016, 6, 39171. [Google Scholar] [CrossRef] [PubMed]
- Hodara, R.; Norris, E.H.; Giasson, B.I.; Mishizen-Eberz, A.J.; Lynch, D.R.; Lee, V.M.; Ischiropoulos, H. Functional consequences of alpha-synuclein tyrosine nitration: Diminished binding to lipid vesicles and increased fibril formation. J. Biol. Chem. 2004, 279, 47746–47753. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bell, R.; Vendruscolo, M. Modulation of the Interactions Between α-Synuclein and Lipid Membranes by Post-translational Modifications. Front Neurol. 2021, 12, 661117. [Google Scholar] [CrossRef]
- Stefanis, L. α-Synuclein in Parkinson’s disease. Cold Spring Harb. Perspect. Med. 2012, 2, a009399. [Google Scholar] [CrossRef] [Green Version]
- Dias, V.; Junn, E.; Mouradian, M.M. The role of oxidative stress in Parkinson’s disease. J. Parkinsons Dis. 2013, 3, 461–491. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hwang, O. Role of oxidative stress in Parkinson’s disease. Exp. Neurobiol. 2013, 22, 11–17. [Google Scholar] [CrossRef] [Green Version]
- Cui, H.; Kong, Y.; Zhang, H. Oxidative stress, mitochondrial dysfunction, and aging. J. Signal Transduct. 2012, 2012, 646354. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huang, M.L.; Chiang, S.; Kalinowski, D.S.; Bae, D.H.; Sahni, S.; Richardson, D.R. The Role of the Antioxidant Response in Mitochondrial Dysfunction in Degenerative Diseases: Cross-Talk between Antioxidant Defense, Autophagy, and Apoptosis. Oxid Med. Cell Longev. 2019, 2019, 6392763. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Oliveira, L.M.A.; Gasser, T.; Edwards, R.; Zweckstetter, M.; Melki, R.; Stefanis, L.; Lashuel, H.A.; Sulzer, D.; Vekrellis, K.; Halliday, G.M.; et al. Alpha-synuclein research: Defining strategic moves in the battle against Parkinson’s disease. NPJ Parkinsons Dis. 2021, 7, 65. [Google Scholar] [CrossRef] [PubMed]
- Juárez Olguín, H.; Calderón Guzmán, D.; Hernández García, E.; Barragán Mejía, G. The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress. Oxid. Med. Cell. Longev. 2016, 2016, 9730467. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Asanuma, M.; Miyazaki, I.; Ogawa, N. Dopamine- or L-DOPA-induced neurotoxicity: The role of dopamine quinone formation and tyrosinase in a model of Parkinson’s disease. Neurotox. Res. 2003, 5, 165–176. [Google Scholar] [CrossRef] [PubMed]
- Ballatori, N.; Krance, S.M.; Notenboom, S.; Shi, S.; Tieu, K.; Hammond, C.L. Glutathione dysregulation and the etiology and progression of human diseases. Biol. Chem. 2009, 390, 191–214. [Google Scholar] [CrossRef] [Green Version]
- Martin, H.L.; Teismann, P. Glutathione--a review on its role and significance in Parkinson’s disease. FASEB J. 2009, 23, 3263–3272. [Google Scholar] [CrossRef] [Green Version]
- Lotharius, J.; Barg, S.; Wiekop, P.; Lundberg, C.; Raymon, H.K.; Brundin, P. Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line. J. Biol. Chem. 2002, 277, 38884–38894. [Google Scholar] [CrossRef] [Green Version]
- Umek, N.; Geršak, B.; Vintar, N.; Šoštarič, M.; Mavri, J. Dopamine Autoxidation Is Controlled by Acidic pH. Front. Mol. Neurosci. 2018, 11, 467. [Google Scholar] [CrossRef] [Green Version]
- Ingelsson, M. Alpha-Synuclein Oligomers-Neurotoxic Molecules in Parkinson’s Disease and Other Lewy Body Disorders. Front Neurosci. 2016, 10, 408. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Emanuele, M.; Chieregatti, E. Mechanisms of alpha-synuclein action on neurotransmission: Cell-autonomous and non-cell autonomous role. Biomolecules 2015, 5, 865–892. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- German, C.L.; Baladi, M.G.; McFadden, L.M.; Hanson, G.R.; Fleckenstein, A.E. Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease. Pharmacol. Rev. 2015, 67, 1005–1024. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tabrez, S.; Jabir, N.R.; Shakil, S.; Greig, N.H.; Alam, Q.; Abuzenadah, A.M.; Damanhouri, G.A.; Kamal, M.A. A synopsis on the role of tyrosine hydroxylase in Parkinson’s disease. CNS Neurol. Disord. Drug Targets 2012, 11, 395–409. [Google Scholar] [CrossRef]
- Rantham Prabhakara, J.P.; Feist, G.; Thomasson, S.; Thompson, A.; Schommer, E.; Ghribi, O. Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on tyrosine hydroxylase and alpha-synuclein in human neuroblastoma SH-SY5Y cells. J. Neurochem. 2008, 107, 1722–1729. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Perez, R.G.; Waymire, J.C.; Lin, E.; Liu, J.J.; Guo, F.; Zigmond, M.J. A role for alpha-synuclein in the regulation of dopamine biosynthesis. J. Neurosci. 2002, 22, 3090–3099. [Google Scholar] [CrossRef] [PubMed]
- Mor, D.E.; Ugras, S.E.; Daniels, M.J.; Ischiropoulos, H. Dynamic structural flexibility of α-synuclein. Neurobiol. Dis. 2016, 88, 66–74. [Google Scholar] [CrossRef] [Green Version]
- Dehay, B.; Bourdenx, M.; Gorry, P.; Przedborski, S.; Vila, M.; Hunot, S.; Singleton, A.; Olanow, C.W.; Merchant, K.M.; Bezard, E.; et al. Targeting α-synuclein for treatment of Parkinson’s disease: Mechanistic and therapeutic considerations. Lancet Neurol. 2015, 14, 855–866. [Google Scholar] [CrossRef] [Green Version]
- Li, J.; Zhu, M.; Manning-Bog, A.B.; Di Monte, D.A.; Fink, A.L. Dopamine and L-dopa disaggregate amyloid fibrils: Implications for Parkinson’s and Alzheimer’s disease. FASEB J. 2004, 18, 962–964. [Google Scholar] [CrossRef]
- Cappa, i.R.; Leck, S.L.; Tew, D.J.; Williamson, N.A.; Smith, D.P.; Galatis, D.; Sharples, R.A.; Curtain, C.C.; Ali, F.E.; Cherny, R.A.; et al. Dopamine promotes alpha-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway. FASEB J. 2005, 19, 1377–1379. [Google Scholar] [CrossRef] [PubMed]
- Ariesandi, W.; Chang, C.F.; Chen, T.E.; Chen, Y.R. Temperature-dependent structural changes of Parkinson’s alpha-synuclein reveal the role of pre-existing oligomers in alpha-synuclein fibrillization. PLoS ONE 2013, 8, e53487. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pham, C.L.; Cappai, R. The interplay between lipids and dopamine on α-synuclein oligomerization and membrane binding. Biosci. Rep. 2013, 33, e00074. [Google Scholar] [CrossRef] [PubMed]
- Luth, E.S.; Bartels, T.; Dettmer, U.; Kim, N.C.; Selkoe, D.J. Purification of α-synuclein from human brain reveals an instability of endogenous multimers as the protein approaches purity. Biochemistry 2015, 54, 279–292. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mor, D.E.; Daniels, M.J.; Ischiropoulos, H. The usual suspects, dopamine and alpha-synuclein, conspire to cause neurodegeneration. Mov. Disord. 2019, 34, 167–179. [Google Scholar] [CrossRef]
- Maguire-Zeiss, K.A.; Short, D.W.; Federoff, H.J. Synuclein, dopamine and oxidative stress: Co-conspirators in Parkinson’s disease? Brain Res. Mol. Brain Res. 2005, 134, 18–23. [Google Scholar] [CrossRef]
- Sulzer, D. Clues to how alpha-synuclein damages neurons in Parkinson’s disease. Mov. Disord. 2010, 25 (Suppl. 1), S27–S31. [Google Scholar] [CrossRef] [Green Version]
- He, S.; Wang, F.; Yung, K.K.L.; Zhang, S.; Qu, S. Effects of α-Synuclein-Associated Post-Translational Modifications in Parkinson’s Disease. ACS Chem. Neurosci. 2021, 12, 1061–1071. [Google Scholar] [CrossRef]
- Volles, M.J.; Lansbury, P.T. 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]
- Luk, K.C.; Kehm, V.; Carroll, J.; Zhang, B.; O’Brien, P.; Trojanowski, J.Q.; Lee, V.M. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 2012, 338, 949–953. [Google Scholar] [CrossRef] [Green Version]
- Hashimoto, M.; Rockenstein, E.; Crews, L.; Masliah, E. Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases. Neuromolecular. Med. 2003, 4, 21–36. [Google Scholar] [CrossRef]
- Levine, P.M.; Galesic, A.; Balana, A.T.; Mahul-Mellier, A.L.; Navarro, M.X.; De Leon, C.A.; Lashuel, H.A.; Pratt, M.R. α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease. Proc. Natl. Acad. Sci. USA 2019, 116, 1511–1519. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Krumova, P.; Meulmeester, E.; Garrido, M.; Tirard, M.; Hsiao, H.H.; Bossis, G.; Urlaub, H.; Zweckstetter, M.; Kügler, S.; Melchior, F.; et al. Sumoylation inhibits alpha-synuclein aggregation and toxicity. J. Cell Biol. 2011, 194, 49–60. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Savyon, M.; Engelender, S. SUMOylation in α-Synuclein Homeostasis and Pathology. Front. Aging Neurosci. 2020, 12, 167. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.T.; Wheeler, T.C.; Li, L.; Chin, L.S. Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Hum. Mol. Genet. 2008, 17, 906–917. [Google Scholar] [CrossRef]
- Rott, R.; Szargel, R.; Shani, V.; Hamza, H.; Savyon, M.; Abd Elghani, F.; Bandopadhyay, R.; Engelender, S. SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation. Proc. Natl Acad. Sci. USA 2017, 114, 13176–13181. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Baba, M.; Nakajo, S.; Tu, P.H.; Tomita, T.; Nakaya, K.; Lee, V.M.; Trojanowski, J.Q.; Iwatsubo, T. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am. J. Pathol. 1998, 152, 879–884. [Google Scholar]
- Campbell, B.C.; McLean, C.A.; Culvenor, J.G.; Gai, W.P.; Blumbergs, P.C.; Jäkälä, P.; Beyreuther, K.; Masters, C.L.; Li, Q.X. The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease. J. Neurochem. 2001, 76, 87–96. [Google Scholar] [CrossRef]
- Kasai, T.; Tokuda, T.; Yamaguchi, N.; Watanabe, Y.; Kametani, F.; Nakagawa, M.; Mizuno, T. Cleavage of normal and pathological forms of alpha-synuclein by neurosin in vitro. Neurosci. Lett. 2008, 436, 52–56. [Google Scholar] [CrossRef]
- Mishizen-Eberz, A.J.; Norris, E.H.; Giasson, B.I.; Hodara, R.; Ischiropoulos, H.; Lee, V.M.; Trojanowski, J.Q.; Lynch, D.R. Cleavage of alpha-synuclein by calpain: Potential role in degradation of fibrillized and nitrated species of alpha-synuclein. Biochemistry 2005, 44, 7818–7829. [Google Scholar] [CrossRef]
- Iwata, A.; Maruyama, M.; Akagi, T.; Hashikawa, T.; Kanazawa, I.; Tsuji, S.; Nukina, N. Alpha-synuclein degradation by serine protease neurosin: Implication for pathogenesis of synucleinopathies. Hum. Mol. Genet. 2003, 12, 2625–2635. [Google Scholar] [CrossRef] [Green Version]
- Mishizen-Eberz, A.J.; Guttmann, R.P.; Giasson, B.I.; Day, G.A.; Hodara, R.; Ischiropoulos, H.; Lee, V.M.; Trojanowski, J.Q.; Lynch, D.R. Distinct cleavage patterns of normal and pathologic forms of alpha-synuclein by calpain I in vitro. J. Neurochem. 2003, 86, 836–847. [Google Scholar] [CrossRef]
- Mor, D.E.; Tsika, E.; Mazzulli, J.R.; Gould, N.S.; Kim, H.; Daniels, M.J.; Doshi, S.; Gupta, P.; Grossman, J.L.; Tan, V.X.; et al. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration. Nat. Neurosci. 2017, 20, 1560–1568. [Google Scholar] [CrossRef] [PubMed]
- Deleersnijder, A.; Gerard, M.; Debyser, Z.; Baekelandt, V. The remarkable conformational plasticity of alpha-synuclein: Blessing or curse? Trends Mol. Med. 2013, 19, 368–377. [Google Scholar] [CrossRef] [PubMed]
- Weinreb, P.H.; Zhen, W.; Poon, A.W.; Conway, K.A.; Lansbury, P.T. NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 1996, 35, 13709–13715. [Google Scholar] [CrossRef] [PubMed]
- 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 2015, 112, 9596–9601. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lemkau, L.R.; Comellas, G.; Lee, S.W.; Rikardsen, L.K.; Woods, W.S.; George, J.M.; Rienstra, C.M. Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson’s disease associated mutations A53T and E46K. PLoS ONE 2013, 8, e49750. [Google Scholar] [CrossRef] [PubMed]
- Zarranz, J.J.; Alegre, J.; Gómez-Esteban, J.C.; Lezcano, E.; Ros, R.; Ampuero, I.; Vidal, L.; Hoenicka, J.; Rodriguez, O.; Atarés, B.; et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 2004, 55, 164–173. [Google Scholar] [CrossRef] [PubMed]
- Cascella, R.; Chen, S.W.; Bigi, A.; Camino, J.D.; Xu, C.K.; Dobson, C.M.; Chiti, F.; Cremades, N.; Cecchi, C. The release of toxic oligomers from α-synuclein fibrils induces dysfunction in neuronal cells. Nat. Commun. 2021, 12, 1814. [Google Scholar] [CrossRef] [PubMed]
- 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. 2007, 171, 2000–2011. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sharon, R.; Bar-Joseph, I.; Frosch, M.P.; Walsh, D.M.; Hamilton, J.A.; Selkoe, D.J. The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson’s disease. Neuron 2003, 37, 583–595. [Google Scholar] [CrossRef] [Green Version]
- Tanji, K.; Mori, F.; Mimura, J.; Itoh, K.; Kakita, A.; Takahashi, H. Proteinase K-resistant alpha-synuclein is deposited in presynapses in human Lewy body disease and A53T alpha-synuclein transgenic mice. Acta Neuropathol. 2010, 120, 145–154. [Google Scholar] [CrossRef] [PubMed]
- Snead, D.; Eliezer, D. Alpha-synuclein function and dysfunction on cellular membranes. Exp. Neurobiol. 2014, 23, 292–313. [Google Scholar] [CrossRef] [Green Version]
- 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] [Green Version]
- Ferreon, A.C.; Gambin, Y.; Lemke, E.A.; Deniz, A.A. Interplay of alpha-synuclein binding and conformational switching probed by single-molecule fluorescence. Proc. Natl. Acad. Sci. USA 2009, 106, 5645–5650. [Google Scholar] [CrossRef] [Green Version]
- Buell, A.K.; Galvagnion, C.; Gaspar, R.; Sparr, E.; Vendruscolo, M.; Knowles, T.P.; Linse, S.; Dobson, C.M. Solution conditions determine the relative importance of nucleation and growth processes in α-synuclein aggregation. Proc. Natl. Acad. Sci. USA 2014, 111, 7671–7676. [Google Scholar] [CrossRef] [Green Version]
- Galvagnion, C.; Buell, A.K.; Meisl, G.; Michaels, T.C.; Vendruscolo, M.; Knowles, T.P.; Dobson, C.M. Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation. Nat. Chem. Biol. 2015, 11, 229–234. [Google Scholar] [CrossRef] [Green Version]
- Lashuel, H.A.; Overk, C.R.; Oueslati, A.; Masliah, E. The many faces of α-synuclein: From structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 2013, 14, 38–48. [Google Scholar] [CrossRef] [Green Version]
- Winner, B.; Jappelli, R.; Maji, S.K.; Desplats, P.A.; Boyer, L.; Aigner, S.; Hetzer, C.; Loher, T.; Vilar, M.; Campioni, S.; et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc. Natl. Acad. Sci. USA 2011, 108, 4194–4199. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pasanen, P.; Myllykangas, L.; Siitonen, M.; Raunio, A.; Kaakkola, S.; Lyytinen, J.; Tienari, P.J.; Pöyhönen, 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] [PubMed]
- Pieri, L.; Madiona, K.; Bousset, L.; Melki, R. Fibrillar α-synuclein and huntingtin exon 1 assemblies are toxic to the cells. Biophys. J. 2012, 102, 2894–2905. [Google Scholar] [CrossRef] [Green Version]
- Ghiglieri, V.; Calabrese, V.; Calabresi, P. Alpha-Synuclein: From Early Synaptic Dysfunction to Neurodegeneration. Front. Neurol. 2018, 9, 295. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Alam, P.; Bousset, L.; Melki, R.; Otzen, D.E. α-synuclein oligomers and fibrils: A spectrum of species, a spectrum of toxicities. J. Neurochem. 2019, 150, 522–534. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kumar, S.T.; Jagannath, S.; Francois, C.; Vanderstichele, H.; Stoops, E.; Lashuel, H.A. How specific are the conformation-specific α-synuclein antibodies? Characterization and validation of 16 α-synuclein conformation-specific antibodies using well-characterized preparations of α-synuclein monomers, fibrils and oligomers with distinct structures and morphology. Neurobiol. Dis. 2020, 146, 105086. [Google Scholar] [PubMed]
- Fields, C.R.; Bengoa-Vergniory, N.; Wade-Martins, R. Targeting Alpha-Synuclein as a Therapy for Parkinson’s Disease. Front. Mol. Neurosci. 2019, 12, 299. [Google Scholar] [CrossRef] [Green Version]
- Bousset, L.; Pieri, L.; Ruiz-Arlandis, G.; Gath, J.; Jensen, P.H.; Habenstein, B.; Madiona, K.; Olieric, V.; Böckmann, A.; Meier, B.H.; et al. Structural and functional characterization of two alpha-synuclein strains. Nat. Commun. 2013, 4, 2575. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guo, J.L.; Covell, D.J.; Daniels, J.P.; Iba, M.; Stieber, A.; Zhang, B.; Riddle, D.M.; Kwong, L.K.; Xu, Y.; Trojanowski, J.Q.; et al. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 2013, 154, 103–117. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Spillantini, M.G.; Crowther, R.A.; Jakes, R.; Cairns, N.J.; Lantos, P.L.; Goedert, M. Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci. Lett. 1998, 251, 205–208. [Google Scholar] [CrossRef]
- 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] [Green Version]
- Outeiro, T.F.; Lindquist, S. Yeast cells provide insight into alpha-synuclein biology and pathobiology. Science 2003, 302, 1772–1775. [Google Scholar] [CrossRef] [Green Version]
- Volpicelli-Daley, L.A.; Gamble, K.L.; Schultheiss, C.E.; Riddle, D.M.; West, A.B.; Lee, V.M. Formation of α-synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomes. Mol. Biol. Cell 2014, 25, 4010–4023. [Google Scholar] [CrossRef] [PubMed]
- Volpicelli-Daley, L.A. Effects of α-synuclein on axonal transport. Neurobiol. Dis. 2017, 105, 321–327. [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] [Green Version]
- 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] [PubMed] [Green Version]
- Chandra, S.; Gallardo, G.; Fernández-Chacón, R.; Schlüter, O.M.; Südhof, T.C. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 2005, 123, 383–396. [Google Scholar] [CrossRef]
- Eisbach, S.E.; Outeiro, T.F. Alpha-synuclein and intracellular trafficking: Impact on the spreading of Parkinson’s disease pathology. J. Mol. Med. 2013, 91, 693–703. [Google Scholar] [CrossRef]
- Abeliovich, A.; Schmitz, Y.; Fariñas, I.; Choi-Lundberg, D.; Ho, W.H.; Castillo, P.E.; Shinsky, N.; Verdugo, J.M.; Armanini, M.; Ryan, A.; et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 2000, 25, 239–252. [Google Scholar] [CrossRef] [Green Version]
- Lundblad, M.; Decressac, M.; Mattsson, B.; Björklund, A. Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons. Proc. Natl. Acad. Sci. USA 2012, 109, 3213–3219. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- 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 alpha-synuclein mice: Implications for neurodegenerative disorders. Science 2000, 287, 1265–1269. [Google Scholar] [CrossRef] [PubMed]
- Janezic, S.; Threlfell, S.; Dodson, P.D.; Dowie, M.J.; Taylor, T.N.; Potgieter, D.; Parkkinen, L.; Senior, S.L.; Anwar, S.; Ryan, B.; et al. Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proc. Natl. Acad. Sci. USA 2013, 110, E4016–E4025. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lotharius, J.; Brundin, P. Pathogenesis of Parkinson’s disease: Dopamine, vesicles and alpha-synuclein. Nat. Rev. Neurosci. 2002, 3, 932–942. [Google Scholar] [CrossRef]
- Chen, L.; Xie, Z.; Turkson, S.; Zhuang, X. A53T human α-synuclein overexpression in transgenic mice induces pervasive mitochondria macroautophagy defects preceding dopamine neuron degeneration. J. Neurosci. 2015, 35, 890–905. [Google Scholar] [CrossRef]
- Nakamura, K.; Nemani, V.M.; Azarbal, F.; Skibinski, G.; Levy, J.M.; Egami, K.; Munishkina, L.; Zhang, J.; Gardner, B.; Wakabayashi, J.; et al. Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J. Biol. Chem. 2011, 286, 20710–20726. [Google Scholar] [CrossRef] [Green Version]
- Dauer, W.; Kholodilov, N.; Vila, M.; Trillat, A.C.; Goodchild, R.; Larsen, K.E.; Staal, R.; Tieu, K.; Schmitz, Y.; Yuan, C.A.; et al. Resistance of alpha -synuclein null mice to the parkinsonian neurotoxin MPTP. Proc. Natl. Acad. Sci. USA 2002, 99, 14524–14529. [Google Scholar] [CrossRef] [Green Version]
- Di Maio, R.; Barrett, P.J.; Hoffman, E.K.; Barrett, C.W.; Zharikov, A.; Borah, A.; Hu, X.; McCoy, J.; Chu, C.T.; Burton, E.A.; et al. α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci. Transl. Med. 2016, 8, 342ra78. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zheng, B.; Liao, Z.; Locascio, J.J.; Lesniak, K.A.; Roderick, S.S.; Watt, M.L.; Eklund, A.C.; Zhang-James, Y.; Kim, P.D.; Hauser, M.A.; et al. PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Sci. Transl. Med. 2010, 2, 52ra73. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ryan, S.D.; Dolatabadi, N.; Chan, S.F.; Zhang, X.; Akhtar, M.W.; Parker, J.; Soldner, F.; Sunico, C.R.; Nagar, S.; Talantova, M.; et al. Isogenic human iPSC Parkinson’s model shows nitrosative stress-induced dysfunction in MEF2-PGC1α transcription. Cell 2013, 155, 1351–1364. [Google Scholar] [CrossRef] [Green Version]
- Tardiff, D.F.; Jui, N.T.; Khurana, V.; Tambe, M.A.; Thompson, M.L.; Chung, C.Y.; Kamadurai, H.B.; Kim, H.T.; Lancaster, A.K.; Caldwell, K.A.; et al. Yeast reveal a "druggable" Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons. Science 2013, 342, 979–983. [Google Scholar] [CrossRef] [Green Version]
- Cooper, A.A.; Gitler, A.D.; Cashikar, A.; Haynes, C.M.; Hill, K.J.; Bhullar, B.; Liu, K.; Xu, K.; Strathearn, K.E.; Liu, F.; et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 2006, 313, 324–328. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chung, C.Y.; Khurana, V.; Auluck, P.K.; Tardiff, D.F.; Mazzulli, J.R.; Soldner, F.; Baru, V.; Lou, Y.; Freyzon, Y.; Cho, S.; et al. Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science 2013, 342, 983–987. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Caraveo, G.; Auluck, P.K.; Whitesell, L.; Chung, C.Y.; Baru, V.; Mosharov, E.V.; Yan, X.; Ben-Johny, M.; Soste, M.; Picotti, P.; et al. Calcineurin determines toxic versus beneficial responses to α-synuclein. Proc. Natl. Acad. Sci. USA 2014, 111, E3544–E3552. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bellucci, A.; Navarria, L.; Zaltieri, M.; Falarti, E.; Bodei, S.; Sigala, S.; Battistin, L.; Spillantini, M.; Missale, C.; Spano, P. Induction of the unfolded protein response by α-synuclein in experimental models of Parkinson’s disease. J. Neurochem. 2011, 116, 588–605. [Google Scholar] [CrossRef] [PubMed]
- Colla, E.; Jensen, P.H.; Pletnikova, O.; Troncoso, J.C.; Glabe, C.; Lee, M.K. Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo. J. Neurosci. 2012, 32, 3301–3305. [Google Scholar] [CrossRef] [Green Version]
- Mizushima, N. Autophagy: Process and function. Genes Dev. 2007, 21, 2861–2873. [Google Scholar] [CrossRef] [Green Version]
- Winslow, A.R.; Chen, C.W.; Corrochano, S.; Acevedo-Arozena, A.; Gordon, D.E.; Peden, A.A.; Lichtenberg, M.; Menzies, F.M.; Ravikumar, B.; Imarisio, S.; et al. α-Synuclein impairs macroautophagy: Implications for Parkinson’s disease. J. Cell Biol. 2010, 190, 1023–1037. [Google Scholar] [CrossRef] [Green Version]
- Cuervo, A.M.; Stefanis, L.; Fredenburg, R.; Lansbury, P.T.; Sulzer, D. Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 2004, 305, 1292–1295. [Google Scholar] [CrossRef]
- Martinez-Vicente, M.; Talloczy, Z.; Kaushik, S.; Massey, A.C.; Mazzulli, J.; Mosharov, E.V.; Hodara, R.; Fredenburg, R.; Wu, D.C.; Follenzi, A.; et al. Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J. Clin. Investig. 2008, 118, 777–788. [Google Scholar]
- Mazzulli, J.R.; Xu, Y.H.; Sun, Y.; Knight, A.L.; McLean, P.J.; Caldwell, G.A.; Sidransky, E.; Grabowski, G.A.; Krainc, D. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011, 146, 37–52. [Google Scholar] [CrossRef] [Green Version]
- Mazzulli, J.R.; Zunke, F.; Isacson, O.; Studer, L.; Krainc, D. α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proc. Natl. Acad. Sci. USA 2016, 113, 1931–1936. [Google Scholar] [CrossRef] [Green Version]
- Rousseaux, M.W.; de Haro, M.; Lasagna-Reeves, C.A.; De Maio, A.; Park, J.; Jafar-Nejad, P.; Al-Ramahi, I.; Sharma, A.; See, L.; Lu, N.; et al. TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau. eLife 2016, 5, e19809. [Google Scholar] [CrossRef]
- Kontopoulos, E.; Parvin, J.D.; Feany, M.B. Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum. Mol. Genet. 2006, 15, 3012–3023. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fares, M.B.; Ait-Bouziad, N.; Dikiy, I.; Mbefo, M.K.; Jovičić, 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 α-synuclein, and enhances its secretion and nuclear localization in cells. Hum. Mol. Genet. 2014, 23, 4491–4509. [Google Scholar] [CrossRef] [PubMed]
- Decressac, M.; Mattsson, B.; Weikop, P.; Lundblad, M.; Jakobsson, J.; Björklund, A. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc. Natl. Acad. Sci. USA 2013, 110, E1817–E1826. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Phillips, M.J.; Voeltz, G.K. Structure and function of ER membrane contact sites with other organelles. Nat. Rev. Mol. Cell Biol. 2016, 17, 69–82. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Calì, T.; Ottolini, D.; Negro, A.; Brini, M. α-Synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions. J. Biol. Chem. 2012, 287, 17914–17929. [Google Scholar] [CrossRef] [Green Version]
- Guardia-Laguarta, C.; Area-Gomez, E.; Rüb, C.; Liu, Y.; Magrané, J.; Becker, D.; Voos, W.; Schon, E.A.; Przedborski, S. α-Synuclein is localized to mitochondria-associated ER membranes. J. Neurosci. 2014, 34, 249–259. [Google Scholar] [CrossRef]
- Vicario, M.; Cieri, D.; Brini, M.; Calì, T. The Close Encounter Between Alpha-Synuclein and Mitochondria. Front. Neurosci. 2018, 12, 388. [Google Scholar] [CrossRef] [Green Version]
- Braak, H.; Del Tredici, K.; Rüb, U.; de Vos, R.A.; Jansen Steur, E.N.; Braak, E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 2003, 24, 197–211. [Google Scholar] [CrossRef]
- Braak, H.; Ghebremedhin, E.; Rüb, U.; Bratzke, H.; Del Tredici, K. Stages in the development of Parkinson’s disease-related pathology. Cell. Tissue Res. 2004, 318, 121–134. [Google Scholar] [CrossRef] [PubMed]
- Killinger, B.A.; Kordower, J.H. Spreading of alpha-synuclein-relevant or epiphenomenon? J. Neurochem. 2019, 150, 605–611. [Google Scholar] [CrossRef] [PubMed]
- Bernal-Conde, L.D.; Ramos-Acevedo, R.; Reyes-Hernández, M.A.; Balbuena-Olvera, A.J.; Morales-Moreno, I.D.; Argüero-Sánchez, R.; Schüle, B.; Guerra-Crespo, M. Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles. Front. Neurosci. 2019, 13, 1399. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chu, Y.; Morfini, G.A.; Langhamer, L.B.; He, Y.; Brady, S.T.; Kordower, J.H. Alterations in axonal transport motor proteins in sporadic and experimental Parkinson’s disease. Brain 2012, 135, 2058–2073. [Google Scholar] [CrossRef] [Green Version]
- Prots, I.; Veber, V.; Brey, S.; Campioni, S.; Buder, K.; Riek, R.; Böhm, K.J.; Winner, B. α-Synuclein oligomers impair neuronal microtubule-kinesin interplay. J. Biol. Chem. 2013, 288, 21742–21754. [Google Scholar] [CrossRef] [Green Version]
- Tilve, S.; Difato, F.; Chieregatti, E. Cofilin 1 activation prevents the defects in axon elongation and guidance induced by extracellular alpha-synuclein. Sci. Rep. 2015, 5, 16524. [Google Scholar] [CrossRef] [Green Version]
- Minakaki, G.; Krainc, D.; Burbulla, L.F. The Convergence of Alpha-Synuclein, Mitochondrial, and Lysosomal Pathways in Vulnerability of Midbrain Dopaminergic Neurons in Parkinson’s Disease. Front. Cell. Dev. Biol. 2020, 8, 580634. [Google Scholar] [CrossRef]
- Xu, L.; Pu, J. Alpha-Synuclein in Parkinson’s Disease: From Pathogenetic Dysfunction to Potential Clinical Application. Parkinsons Dis. 2016, 2016, 1720621. [Google Scholar] [CrossRef] [Green Version]
- Thayanidhi, N.; Helm, J.R.; Nycz, D.C.; Bentley, M.; Liang, Y.; Hay, J.C. Alpha-synuclein delays endoplasmic reticulum (ER)-to-Golgi transport in mammalian cells by antagonizing ER/Golgi SNAREs. Mol. Biol. Cell 2010, 21, 1850–1863. [Google Scholar] [CrossRef] [Green Version]
- Ulusoy, A.; Decressac, M.; Kirik, D.; Björklund, A. Viral vector-mediated overexpression of α-synuclein as a progressive model of Parkinson’s disease. Prog. Brain Res. 2010, 184, 89–111. [Google Scholar]
- Volpicelli-Daley, L.A.; Kirik, D.; Stoyka, L.E.; Standaert, D.G.; Harms, A.S. How can rAAV-α-synuclein and the fibril α-synuclein models advance our understanding of Parkinson’s disease? J. Neurochem. 2016, 139 (Suppl. 1), 131–155. [Google Scholar] [CrossRef] [PubMed]
- Xu, S.; Chan, P. Interaction between Neuromelanin and Alpha-Synuclein in Parkinson’s Disease. Biomolecules 2015, 5, 1122–1142. [Google Scholar] [CrossRef] [PubMed]
- Villa, S.; Lombardi, A.; Mangioni, D.; Bozzi, G.; Bandera, A.; Gori, A.; Raviglione, M.C. The COVID-19 pandemic preparedness … or lack thereof: From China to Italy. Glob. Health Med. 2020, 2, 73–77. [Google Scholar] [PubMed] [Green Version]
- Frigerio, R.; Fujishiro, H.; Ahn, T.B.; Josephs, K.A.; Maraganore, D.M.; DelleDonne, A.; Parisi, J.E.; Klos, K.J.; Boeve, B.F.; Dickson, D.W.; et al. Incidental Lewy body disease: Do some cases represent a preclinical stage of dementia with Lewy bodies? Neurobiol. Aging 2011, 32, 857–863. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Auluck, P.K.; Chan, H.Y.; Trojanowski, J.Q.; Lee, V.M.; Bonini, N.M. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 2002, 295, 865–868. [Google Scholar] [CrossRef] [PubMed]
- Ihara, M.; Yamasaki, N.; Hagiwara, A.; Tanigaki, A.; Kitano, A.; Hikawa, R.; Tomimoto, H.; Noda, M.; Takanashi, M.; Mori, H.; et al. Sept4, a component of presynaptic scaffold and Lewy bodies, is required for the suppression of alpha-synuclein neurotoxicity. Neuron 2007, 53, 519–533. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Outeiro, T.F.; Kontopoulos, E.; Altmann, S.M.; Kufareva, I.; Strathearn, K.E.; Amore, A.M.; Volk, C.B.; Maxwell, M.M.; Rochet, J.C.; McLean, P.J.; et al. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 2007, 317, 516–519. [Google Scholar] [CrossRef] [PubMed]
- Li, W.; Lesuisse, C.; Xu, Y.; Troncoso, J.C.; Price, D.L.; Lee, M.K. Stabilization of alpha-synuclein protein with aging and familial parkinson’s disease-linked A53T mutation. J. Neurosci. 2004, 24, 7400–7409. [Google Scholar] [CrossRef] [Green Version]
- Bender, A.; Krishnan, K.J.; Morris, C.M.; Taylor, G.A.; Reeve, A.K.; Perry, R.H.; Jaros, E.; Hersheson, J.S.; Betts, J.; Klopstock, T.; et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet. 2006, 38, 515–517. [Google Scholar] [CrossRef]
- Vilchez, D.; Saez, I.; Dillin, A. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat. Commun. 2014, 5, 5659. [Google Scholar] [CrossRef]
- Wong, Y.C.; Holzbaur, E.L. Autophagosome dynamics in neurodegeneration at a glance. J. Cell Sci. 2015, 128, 1259–1267. [Google Scholar] [CrossRef] [Green Version]
- Finkel, T.; Holbrook, N.J. Oxidants, oxidative stress and the biology of ageing. Nature 2000, 408, 239–247. [Google Scholar] [CrossRef]
- Zecca, L.; Casella, L.; Albertini, A.; Bellei, C.; Zucca, F.A.; Engelen, M.; Zadlo, A.; Szewczyk, G.; Zareba, M.; Sarna, T. Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson’s disease. J. Neurochem. 2008, 106, 1866–1875. [Google Scholar] [PubMed]
- Lee, H.J.; Suk, J.E.; Patrick, C.; Bae, E.J.; Cho, J.H.; Rho, S.; Hwang, D.; Masliah, E.; Lee, S.J. Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J. Biol. Chem. 2010, 285, 9262–9272. [Google Scholar] [CrossRef] [Green Version]
- Woerman, A.L.; Watts, J.C.; Aoyagi, A.; Giles, K.; Middleton, L.T.; Prusiner, S.B. α-Synuclein: Multiple System Atrophy Prions. Cold Spring Harb. Perspect. Med. 2018, 8, a024588. [Google Scholar] [CrossRef]
- Ubhi, K.; Low, P.; Masliah, E. Multiple system atrophy: A clinical and neuropathological perspective. Trends Neurosci. 2011, 34, 581–590. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ouchi, Y.; Yoshikawa, E.; Sekine, Y.; Futatsubashi, M.; Kanno, T.; Ogusu, T.; Torizuka, T. Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann. Neurol. 2005, 57, 168–175. [Google Scholar] [CrossRef]
- Gao, H.M.; Kotzbauer, P.T.; Uryu, K.; Leight, S.; Trojanowski, J.Q.; Lee, V.M. Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J. Neurosci. 2008, 28, 7687–7698. [Google Scholar] [CrossRef] [PubMed]
- Harms, A.S.; Cao, S.; Rowse, A.L.; Thome, A.D.; Li, X.; Mangieri, L.R.; Cron, R.Q.; Shacka, J.J.; Raman, C.; Standaert, D.G. MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J. Neurosci. 2013, 33, 9592–9600. [Google Scholar] [CrossRef] [PubMed]
- Daniele, S.G.; Béraud, D.; Davenport, C.; Cheng, K.; Yin, H.; Maguire-Zeiss, K.A. Activation of MyD88-dependent TLR1/2 signaling by misfolded α-synuclein, a protein linked to neurodegenerative disorders. Sci. Signal. 2015, 8, ra45. [Google Scholar] [CrossRef] [Green Version]
- Kim, C.; Ho, D.H.; Suk, J.E.; You, S.; Michael, S.; Kang, J.; Joong Lee, S.; Masliah, E.; Hwang, D.; Lee, H.J.; et al. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 2013, 4, 1562. [Google Scholar] [CrossRef] [Green Version]
- Wang, S.; Chu, C.H.; Stewart, T.; Ginghina, C.; Wang, Y.; Nie, H.; Guo, M.; Wilson, B.; Hong, J.S.; Zhang, J. α-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation. Proc. Natl. Acad. Sci. USA 2015, 112, E1926–E1935. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thome, A.D.; Harms, A.S.; Volpicelli-Daley, L.A.; Standaert, D.G. microRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease. J. Neurosci. 2016, 36, 2383–2390. [Google Scholar] [CrossRef]
- Ejlerskov, P.; Hultberg, J.G.; Wang, J.; Carlsson, R.; Ambjørn, M.; Kuss, M.; Liu, Y.; Porcu, G.; Kolkova, K.; Friis Rundsten, C.; et al. Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson’s Disease-like Dementia. Cell 2015, 163, 324–339. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hamza, T.H.; Zabetian, C.P.; Tenesa, A.; Laederach, A.; Montimurro, J.; Yearout, D.; Kay, D.M.; Doheny, K.F.; Paschall, J.; Pugh, E.; et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat. Genet. 2010, 42, 781–785. [Google Scholar] [CrossRef]
- Larson, M.E.; Sherman, M.A.; Greimel, S.; Kuskowski, M.; Schneider, J.A.; Bennett, D.A.; Lesné, S.E. Soluble α-synuclein is a novel modulator of Alzheimer’s disease pathophysiology. J. Neurosci. 2012, 32, 10253–10266. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Masliah, E.; Rockenstein, E.; Veinbergs, I.; Sagara, Y.; Mallory, M.; Hashimoto, M.; Mucke, L. beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease. Proc. Natl. Acad. Sci. USA 2001, 98, 12245–12250. [Google Scholar] [CrossRef] [Green Version]
- Yoshimoto, M.; Iwai, A.; Kang, D.; Otero, D.A.; Xia, Y.; Saitoh, T. NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. Proc. Natl. Acad. Sci. USA 1995, 92, 9141–9145. [Google Scholar] [CrossRef] [Green Version]
- Bachhuber, T.; Katzmarski, N.; McCarter, J.F.; Loreth, D.; Tahirovic, S.; Kamp, F.; Abou-Ajram, C.; Nuscher, B.; Serrano-Pozo, A.; Müller, A.; et al. Inhibition of amyloid-β plaque formation by α-synuclein. Nat. Med. 2015, 21, 802–807. [Google Scholar] [CrossRef]
- Zhang, X.; Gao, F.; Wang, D.; Li, C.; Fu, Y.; He, W.; Zhang, J. Tau Pathology in Parkinson’s Disease. Front. Neurol. 2018, 9, 809. [Google Scholar] [CrossRef] [Green Version]
- Arima, K.; Hirai, S.; Sunohara, N.; Aoto, K.; Izumiyama, Y.; Uéda, K.; Ikeda, K.; Kawai, M. Cellular co-localization of phosphorylated tau- and NACP/alpha-synuclein-epitopes in lewy bodies in sporadic Parkinson’s disease and in dementia with Lewy bodies. Brain Res. 1999, 843, 53–61. [Google Scholar] [CrossRef]
- Haggerty, T.; Credle, J.; Rodriguez, O.; Wills, J.; Oaks, A.W.; Masliah, E.; Sidhu, A. Hyperphosphorylated Tau in an α-synuclein-overexpressing transgenic model of Parkinson’s disease. Eur. J. Neurosci. 2011, 33, 1598–1610. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jaworski, T.; Kügler, S.; Van Leuven, F. Modeling of tau-mediated synaptic and neuronal degeneration in Alzheimer’s disease. Int. J. Alzheimers Dis. 2010, 2010, 573138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Post-Translational Modification | Amino Acid Residues |
---|---|
Phosphorylation | S129 [43] |
Nitration | Y39, Y125, Y133, Y136 [60] |
Ubiquitination | K10, K12, K21, K23, K34, K43, K96 [97] |
Sumoylation | K96, K102 [98] |
O-GlcNAcylation | T72, T75, T81, S87 [94] |
Truncation | K58, K80, K97, V74 [104] |
Dopamine | E83, Y125EMPS129 [105] |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Shan, F.Y.; Fung, K.-M.; Zieneldien, T.; Kim, J.; Cao, C.; Huang, J.H. Examining the Toxicity of α-Synuclein in Neurodegenerative Disorders. Life 2021, 11, 1126. https://0-doi-org.brum.beds.ac.uk/10.3390/life11111126
Shan FY, Fung K-M, Zieneldien T, Kim J, Cao C, Huang JH. Examining the Toxicity of α-Synuclein in Neurodegenerative Disorders. Life. 2021; 11(11):1126. https://0-doi-org.brum.beds.ac.uk/10.3390/life11111126
Chicago/Turabian StyleShan, Frank Y., Kar-Ming Fung, Tarek Zieneldien, Janice Kim, Chuanhai Cao, and Jason H. Huang. 2021. "Examining the Toxicity of α-Synuclein in Neurodegenerative Disorders" Life 11, no. 11: 1126. https://0-doi-org.brum.beds.ac.uk/10.3390/life11111126