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Alpha Synuclein and Parkinson’s Disease

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Pathology, Prevention and Therapeutics of Neurodegenerative Disease

Abstract

α-Synuclein predominantly expressed in the brain is a small acidic protein containing three domains namely N-terminal lipid-binding α-helix, amyloid-binding central domain (NAC), and C-terminal acidic tail. The physiological functions of this protein remain poorly understood. α-Synuclein localizes specifically to the nerve terminal and has been extensively described to take active task in the regulation of release of neurotransmitter at the presynapse in brain. Accumulating evidence suggests that prefibrillar species, and aggregated form of α-synuclein, are accountable for the pathogenicity of Parkinson’s disease (PD). Larger oligomers of α-synuclein exhibited to impair many functions of neuronal cells including: impairment of synaptic functions, impairment of the mitochondrial and the endoplasmic reticulum functions, and the impairment of protein degradation pathways. Oligomers/protofibrils once accumulated inside or outside cells may cause a lethal effect on the synapse, which may cause disruption of the neurotransmission. The oligomeric α-synuclein species has also the property of spreading between neuronal cells, either as drifting proteins or via extracellular vesicles, and thus spreading the toxic effects in different parts of the brain. Although several mutations in α-synuclein gene have been known that causes familial PD in human, the mechanisms that elevate the accumulation and aggregation of α-synuclein protein are not well addressed. Considering of the mechanism of aggregation of α-synuclein protein and targeting the toxic functions of this protein in brain cells including dysregulated mitochondrial functions may lead to novel therapeutic approaches in Parkinson’s disease.

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References

  1. Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013.

    Article  PubMed  Google Scholar 

  2. Lewy FH. Paralysis agitans. I Pathologische anatomie. In: Lewandowsky M, editor. Handbuch der neurologie. Berlin: Springer; 1912. p. 920–33.

    Google Scholar 

  3. Tanaka M, Kim YM, Lee G, et al. Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem. 2004;279:4625–31.

    Article  CAS  PubMed  Google Scholar 

  4. Vargas KJ, Makani S, Davis T, et al. Synucleins regulate the kinetics of synaptic vesicle endocytosis. J Neurosci. 2014;34:9364–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rosborough K, Patel N, Kalia LV. α-Synuclein and Parkinsonism: updates and future perspectives. Curr Neurol Neurosci Rep. 2017;17(4):31.

    Article  CAS  PubMed  Google Scholar 

  6. Krüger R, Kuhn W, Müller T, et al. Ala 30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet. 1998;18:106–8.

    Article  PubMed  Google Scholar 

  7. Zarranz JJ, Alegre J, Gómez-Esteban JC, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 2004;55:164–73.

    Article  CAS  PubMed  Google Scholar 

  8. Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–40.

    Article  CAS  PubMed  Google Scholar 

  9. Lavedan C. The synuclein family. Genome Res. 1998;8:871–80.

    Article  CAS  PubMed  Google Scholar 

  10. Clayton DF, George JM. Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res. 1999;58:120–9.

    Article  CAS  PubMed  Google Scholar 

  11. El-Agnaf OM, Salem SA, Paleologou KE, et al. α-Synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB J. 2003;17:1945–7.

    Article  CAS  PubMed  Google Scholar 

  12. Tokuda T, Qureshi MM, Ardah MT, et al. Detection of elevated levels of α-synuclein oligomers in CSF from patients with Parkinson disease. Neurology. 2010;75:1766–72.

    Article  CAS  PubMed  Google Scholar 

  13. Clayton DF, George JM. The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci. 1998;21:249–54.

    Article  CAS  PubMed  Google Scholar 

  14. Goedert M. Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci. 2001;2:492–501.

    Article  CAS  PubMed  Google Scholar 

  15. Burre J, Vivona S, Diao J, et al. Properties of native brain alpha-synuclein. Nature. 2013;498:E4–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chinta SJ, Mallajosyula JK, Rane A, et al. Mitochondrial α-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci Lett. 2010;486:235–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li J-Y, Elisabet E, Holton JL, et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med. 2008;14:501–3.

    Article  CAS  PubMed  Google Scholar 

  18. Christian H, Elodie A, Ann-Louise B, et al. α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest. 2011;121:715–25.

    Article  CAS  Google Scholar 

  19. Fauvet B, Mbefo MK, Fares MB, et al. Alpha-synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. J Biol Chem. 2012;287:15345–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jakes R, Spillantini MG, Goedert M. Identification of two distinct synucleins from human brain. FEBS Lett. 1994;345:27–32.

    Article  CAS  PubMed  Google Scholar 

  21. Dehay B, Bourdenx M, Gorry P, et al. Targeting α-synuclein for treatment of Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol. 2015;14:855–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Giasson BI, Murray IVJ, Trojanowski JQ, et al. A hydrophobic stretch of 12 amino acid residues in the middle of α-synuclein is essential for filament assembly. J Biol Chem. 2001;276:2380–6.

    Article  CAS  PubMed  Google Scholar 

  23. Reish HEA, Standaert DG. Role of α-synuclein in inducing innate and adaptive immunity in Parkinson disease. J Parkinsons Dis. 2015;5:1–19.

    Google Scholar 

  24. Kostas V, Maria X, Evangelia E, et al. Pathological roles of α-synuclein in neurological disorders. Lancet Neurol. 2011;10:1015–25.

    Article  CAS  Google Scholar 

  25. Jenco JM, Rawlingson A, Daniels B, et al. Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha- and beta-synucleins. Biochemistry. 1998;37:4901–9.

    Article  CAS  PubMed  Google Scholar 

  26. Abeliovich A, Schmitz Y, Farinas I, et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000;25:239–52.

    Article  CAS  PubMed  Google Scholar 

  27. Chandra S, Gallardo G, Fernandez-Chacon R, et al. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell. 2005;123:383–96.

    Article  CAS  PubMed  Google Scholar 

  28. Martin LJ, Pan Y, Price AC, et al. Parkinson’s disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci. 2006;26:41–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kamp F, Exner N, Lutz AK, et al. Inhibition of mitochondrial fusion by alpha-synuclein is rescued by PINK1, Parkin and DJ-1. EMBO J. 2010;29:3571–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cooper AA, Gitler AD, Cashikar A, et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science. 2006;313:324–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Thayanidhi N, Helm JR, Nycz DC, et al. Alpha-synuclein delays endoplasmic reticulum (ER)-to-Golgi transport in mammalian cells by antagonizing ER/Golgi SNAREs. Mol Biol Cell. 2010;21:1850–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Martinez-Vicente M, Vila M. Alpha-synuclein and protein degradation pathways in Parkinson’s disease: a pathological feed-back loop. Exp Neurol. 2013;247:308–13.

    Article  CAS  PubMed  Google Scholar 

  33. Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24:197–211.

    Article  PubMed  Google Scholar 

  34. Borghi R, Marchese R, Negro A, et al. Full length alpha-synuclein is present in cerebrospinal fluid from Parkinson’s disease and normal subjects. Neurosci Lett. 2000;287:65–7.

    Article  CAS  PubMed  Google Scholar 

  35. Sung JY, Park SM, Lee CH, et al. Proteolytic cleavage of extracellular secreted {alpha}-synuclein via matrix metalloproteinases. J Biol Chem. 2005;280:25216–24.

    Article  CAS  PubMed  Google Scholar 

  36. Danzer KM, Ruf WP, Putcha P, et al. Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity. FASEB J. 2011;25:326–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sung JY, Kim J, Paik SR, et al. Induction of neuronal cell death by Rab5A-dependent endocytosis of alpha-synuclein. J Biol Chem. 2001;276:27441–8.

    Article  CAS  PubMed  Google Scholar 

  38. Luk KC, Song C, O’Brien P, et al. Exogenous alpha-synuclein fibrils seed the formation of lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A. 2009;106:20051–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nonaka T, Watanabe ST, Iwatsubo T, et al. Seeded aggregation and toxicity of {alpha}-synuclein and tau: cellular models of neurodegenerative diseases. J Biol Chem. 2010;285:34885–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Auluck PK, Caraveo G, Lindquist S. Alpha-synuclein: membrane interactions and toxicity in Parkinson’s disease. Annu Rev Cell Dev Biol. 2010;26:211–33.

    Article  CAS  PubMed  Google Scholar 

  41. Desplats P, Lee HJ, Bae EJ, et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A. 2009;106:13010–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hansen C, Angot E, Bergstrom AL, et al. Alpha-synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest. 2011;121:715–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kordower JH, Dodiya HB, Kordower AM, et al. Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat. Neurobiol Dis. 2011;43:552–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Maroteaux L, Campanelli JT, Scheller RH. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci. 1988;8:2804–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Withers GS, George JM, Banker GA, et al. Delayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons. Brain Res Dev Brain Res. 1997;99:87–94.

    Article  CAS  PubMed  Google Scholar 

  46. Bendor JT, Logan TP, Edwards RH. The function of alpha-synuclein. Neuron. 2013;79:1044–66.

    Article  CAS  PubMed  Google Scholar 

  47. Burre J, Sharma M, Tsetsenis T, et al. Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010;329:1663–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schoch S, Deák F, Konigstorfer A, et al. SNARE function analyzed in synaptobrevin/VAMP knockout mice. Science. 2001;294:1117–22.

    Article  CAS  PubMed  Google Scholar 

  49. Südhof TC, Rizo J. Synaptic vesicle exocytosis. Cold Spring Harb Perspect Biol. 2011;3:a005637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Diao J, Burré J, Vivona S, et al. Native alpha-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2. elife. 2013;2:e00592.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Kontopoulos E, Parvin JD, Feany MB. Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet. 2006;15:3012–23.

    Article  CAS  PubMed  Google Scholar 

  52. Liu X, Cheng R, Verbitsky M, et al. Genome-wide association study identifies candidate genes for Parkinson’s disease in an Ashkenazi Jewish population. BMC Med Genet. 2011;12:104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gonçalves S, Outeiro TF. Assessing the subcellular dynamics of alpha-synuclein using photoactivation microscopy. Mol Neurobiol. 2013;47:1081–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Desplats P, Spencer B, Crews L, et al. α-Synuclein induces alterations in adult neurogenesis in Parkinson disease models via p53-mediated repression of Notch1. J Biol Chem. 2012;287:31691–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Siddiqui A, Chinta SJ, Mallajosyula JK, et al. Selective binding of nuclear alpha-synuclein to the PGC1alpha promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: implications for Parkinson’s disease. Free Radic Biol Med. 2012;53:993–1003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Jin H, Kanthasamy A, Ghosh A, et al. Alpha-synuclein negatively regulates protein kinase Cdelta expression to suppress apoptosis in dopaminergic neurons by reducing p300 histone acetyltransferase activity. J Neurosci. 2011;31:2035–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Fu H, Subramanian RR, Masters SC. 14-3-3 proteins: structure, function, and regulation. Annu Rev Pharmacol Toxicol. 2000;40:617–47.

    Article  CAS  PubMed  Google Scholar 

  58. Sharma SK, Chorell E, Steneberg P, et al. Insulin-degrading enzyme prevents α-synuclein fibril formation in a nonproteolytical manner. Sci Rep. 2015;5:12531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Park SM, Jung HY, Kim TD, et al. Distinct roles of the N-terminal-binding domain and the C-terminal-solubilizing domain of α-synuclein, a molecular chaperone. Biol Chem. 2002;277:28512–20.

    Article  CAS  Google Scholar 

  60. Zhu M, Qin ZJ, Hu D, et al. Alpha-synuclein can function as an antioxidant preventing oxidation of unsaturated lipid in vesicles. Biochemistry. 2006;45:8135–42.

    Article  CAS  PubMed  Google Scholar 

  61. Latchoumycandane C, Anantharam V, Kitazawa M, et al. Protein kinase Cdelta is a key downstream mediator of manganese-induced apoptosis in dopaminergic neuronal cells. J Pharmacol Exp Ther. 2005;313:46–55.

    Article  CAS  PubMed  Google Scholar 

  62. Peng X, Tehranian R, Dietrich P, et al. Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells. J Cell Sci. 2005;118:3523–30.

    Article  CAS  PubMed  Google Scholar 

  63. Radivojac P, Iakoucheva LM, Oldfield CJ, et al. Intrinsic disorder and functional proteomics. Biophys J. 2007;92:1439–56.

    Article  CAS  PubMed  Google Scholar 

  64. Bertoncini CW, Jung YS, Fernandez CO, et al. Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein. Proc Natl Acad Sci U S A. 2005;102:1430–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Parihar MS, Parihar A, Fujita M, et al. Mitochondrial association of alpha-synuclein causes oxidative stress. Cell Mol Life Sci. 2008;65:1272–84.

    Article  CAS  PubMed  Google Scholar 

  66. Parihar MS, Parihar A, Fujita M, et al. Alpha-synuclein overexpression and aggregation exacerbates impairment of mitochondrial functions by augmenting oxidative stress in human neuroblastoma cells. Int J Biochem Cell Biol. 2009;41:2015–24.

    Article  CAS  PubMed  Google Scholar 

  67. Conway KA, Harper JD, Lansbury PT. Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med. 1998;4:1318–20.

    Article  CAS  PubMed  Google Scholar 

  68. Li J, Uversky VN, Anthony L. Fink effect of familial Parkinson’s disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human α-synuclein. Biochemistry. 2001;40:11604–13.

    Article  CAS  PubMed  Google Scholar 

  69. Greenbaum EA, Graves CL, Mishizen-Eberz AJ, et al. The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem. 2005;280:7800–7.

    Article  CAS  PubMed  Google Scholar 

  70. Burre J, Sharma M, Südhof TC. Systematic mutagenesis of α-synuclein reveals distinct sequence requirements for physiological and pathological activities. J Neurosci. 2012;32:15227–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ghosh D, Mondal M, Mohite GM, et al. The Parkinson’s disease-associated H50Q mutation accelerates α-synuclein aggregation in vitro. Biochemistry. 2013;52:6925–7.

    Article  CAS  PubMed  Google Scholar 

  72. Lazaro DF, Rodrigues EF, Langohr R, et al. Systematic comparison of the effects of alpha-synuclein mutations on its oligomerization and aggregation. PLoS Genet. 2014;10:e1004741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Rutherford NJ, Moore BD, Golde TE, et al. Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of α-synuclein. J Neurochem. 2014;131:859–67.

    Article  CAS  PubMed  Google Scholar 

  74. Sharon R, Bar-Joseph I, Mirick GE, et al. Altered fatty acid composition of dopaminergic neurons expressing alpha-synuclein and human brains with alpha-synucleinopathies. J Biol Chem. 2003;278:49874–81.

    Article  CAS  PubMed  Google Scholar 

  75. Paleologou KE, Kragh CL, Mann DM, et al. Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain. 2009;132:1093–101.

    Article  PubMed  Google Scholar 

  76. Roberts RF, Wade-Martins R, Alegre-Abarrategui J. Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson’s disease brain. Brain. 2015;138:1642–57.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Karpinar DP, Balija MB, Kügler S, et al. Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson’s disease models. EMBO J. 2009;28:3256–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Winner B, Jappelli R, Maji SK, et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A. 2011;108:4194–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Rockenstein E, Nuber S, Overk CR, et al. Accumulation of oligomer-prone α-synuclein exacerbates synaptic and neuronal degeneration in vivo. Brain. 2014;137:1496–513.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Luk KC, Kehm V, Carroll J, et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012;338:949–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Masuda-Suzukake M, Nonaka T, Hosokawa M, et al. Prion-like spreading of pathological α-synuclein in brain. Brain. 2013;136:1128–38.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Recasens A, Dehay B. Alpha-synuclein spreading in Parkinson’s disease. Front Neuroanat. 2014;8:159.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Simon-Sanchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet. 2009;41:1308–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lashuel HA, Overk CR, Oueslati A, et al. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2013;14:38–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chandra S, Fornai F, Kwon HB, et al. Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc Natl Acad Sci U S A. 2004;101:14966–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Luk KC, Kehm VM, Zhang B, et al. Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice. J Exp Med. 2012;209:975–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Brundin P, Li JY, Holton JL, et al. Research in motion: the enigma of Parkinson’s disease pathology spread. Nat Rev Neurosci. 2008;9:741–5.

    Article  CAS  PubMed  Google Scholar 

  88. Christine K, Ana W. Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;2:a008888.

    Google Scholar 

  89. Dawson TM, Ko HS, Dawson VL. Genetic animal models of Parkinson’s disease. Neuron. 2010;66:646–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chesselet MF, Richter F. Modelling of Parkinson’s disease in mice. Lancet Neurol. 2011;10:1108–18.

    Article  PubMed  Google Scholar 

  91. Fujiwara H, Hasegawa M, Dohmae N, et al. Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol. 2002;4:160–4.

    Article  CAS  PubMed  Google Scholar 

  92. Danzer KM, Haasen D, Karow AR, et al. Different species of alpha synuclein oligomers induce calcium influx and seeding. J Neurosci. 2007;27:9220–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Choi BK, Choi MG, Kim JY, et al. Large alpha-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking. Proc Natl Acad Sci U S A. 2013;110:4087–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Diogenes MJ, Dias RB, Rombo DM, et al. Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation. J Neurosci. 2012;32:11750–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kaufmann TJ, Harrison PM, Richardson MJ, et al. Intracellular soluble alpha-synuclein oligomers reduce pyramidal cell excitability. J Physiol. 2016;594:2751–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rockenstein E, Nuber S, Overk CR, et al. Accumulation of oligomer-prone alpha-synuclein exacerbates synaptic and neuronal degenerationin vivo. Brain. 2014;137:1496–513.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Longhena L, Faustini G, Missale C. Contribution of α-synuclein spreading to Parkinson’s disease synaptopathy. Neural Plast. 2017;2017:1–15.

    Article  CAS  Google Scholar 

  98. Di Maio R, Barrett PJ, Hoffman EK, et al. α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci Transl Med. 2016;8:342ra378.

    Google Scholar 

  99. Paillusson S, Gomez-Suaga P, Stoica R, et al. α-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca2+ homeostasis and mitochondrial ATP production. Acta Neuropathol. 2017;134(1):129–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Colla E, Coune P, Liu Y, et al. Endoplasmic reticulum stress is important for the manifestations of alpha-synucleinopathy in vivo. J Neurosci. 2012b;32:3306–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Devi L, Raghavendran V, Prabhu BM, et al. Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem. 2008;283:9089–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Loeb V, Yakunin E, Saada A, et al. The transgenic overexpression of alpha-synuclein and not its related pathology associates with complex I inhibition. J Biol Chem. 2010;285:7334–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lee HJ, Suk JE, Bae EJ, et al. Clearance and deposition of extracellular alpha-synuclein aggregates in microglia. Biochem Biophys Res Commun. 2008;372:423–8.

    Article  CAS  PubMed  Google Scholar 

  104. Lee HJ, Suk JE, Patrick C, et al. Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J Biol Chem. 2010;285:9262–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Zhang W, Wang T, Pei Z, et al. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J. 2005;19:533–42.

    Article  CAS  PubMed  Google Scholar 

  106. Wilms H, Rosenstiel P, Romero-Ramos M, et al. Suppression of MAP kinases inhibits microglial activation and attenuates neuronal cell death induced by alpha-synuclein protofibrils. Int J Immunopathol Pharmacol. 2009;22:897–909.

    Article  CAS  PubMed  Google Scholar 

  107. Nakamura K, Nemani VM, Azarbal F, et al. Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J Biol Chem. 2011;286:20710–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Choubey V, Safiulina D, Vaarmann A, et al. Mutant A53T alpha-synuclein induces neuronal death by increasing mitochondrial autophagy. J Biol Chem. 2011;286:10814–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–7.

    Article  CAS  PubMed  Google Scholar 

  110. Tran HT, Chung CH, Iba M, et al. α-Synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep. 2014;7:2054–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Biology Department, Bellingham Technical College, Bellingham, WA, USA

    Arti Parihar

  2. School of Studies in Zoology and Biotechnology, Vikram University, Ujjain, Madhya Pradesh, India

    Priyanka Parihar & Isha Solanki

  3. School of Studies in Zoology and Biotechnology, Faculty of Life Sciences, Vikram University, Ujjain, Madhya Pradesh, India

    Mordhwaj S. Parihar

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  1. Toxicology and Experimental Medicine Division, CSIR-Central Drug Research Institute, Lucknow, India

    Sarika Singh

  2. Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedar Sinai Medical Center, Los Angeles, CA, USA

    Neeraj Joshi

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Parihar, A., Parihar, P., Solanki, I., Parihar, M.S. (2019). Alpha Synuclein and Parkinson’s Disease. In: Singh, S., Joshi, N. (eds) Pathology, Prevention and Therapeutics of Neurodegenerative Disease. Springer, Singapore. https://doi.org/10.1007/978-981-13-0944-1_1

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