An Overview of Alpha Synuclein Protein and Its Role in Parkinson’s disease

Parkinson’s disease is the most common age-related motor movement disorder. Pathological changes in Parkinson’s disease are the loss of melanin-containing dopaminergic neurons and the detection of inclusion bodies in the cells, which contain alpha-synuclein and ubiquitinated proteins, called as Lewy bodies. In this review; the structure of Lewy bodies, structural features and intracellular localization of α-synuclein protein, intracellular functions and intercellular spread of α-synuclein protein are discussed. The physiological and pathologic features of α-synuclein protein are reviewed based mostly upon review of the literature. α-synuclein has significant functions especially at central nervous system. α-synuclein is a protein that can be found in various areas within the cell, particularly in the presynaptic axon terminals. Under pathologic conditions, cellular accumulation of misfolded α-synuclein oligomers and aggregates are observed in a group of neurodegenerative diseases called synucleinopathies. The mechanisms of how α-synuclein protein takes part in the neurodegeneration process and physiologic roles of the protein have not been fully elucidated yet. It’s important to unravel the secrets of this protein and understand its behaviours in order to improve existing treatment protocols and also to develop new and more effective treatments for Parkinson’s Disease.

PDF

___

[1]Jellinger KA. Neuropathobiology of non-motor symptoms in Parkinson disease. Journal of Neural Transmission. 2015; 122(10): 1429-1440.

[2]Michel PP, Hirsch EC, Hunot S. Understanding dopaminergic cell death pathways in Parkinson disease. Neuron. 2016; 90(4): 675-691.

[3]Alberio T, Lopiano L, Fasano M. Cellular models to investigate biochemical pathways in Parkinson’s disease. FEBS Journal. 2012; 279(7): 1146-1155.

[4]Kaur K, Gill JS, Bansal PK, et al. Neuroinflammation-A major cause for striatal dopaminergic degeneration in Parkinson’s disease. Journal of the neurological sciences. 2017; 381: 308-314.

[5]Engelhardt E, Gomes MdM. Lewy and his inclusion bodies: Discovery and rejection. Dementia & Neuropsychologia. 2017; 11(2): 198-201.

[6]Goedert M, Spillantini MG, Del Tredici K, et al. 100 years of Lewy pathology. Nature Reviews Neurology. 2013; 9(1): 13.

[7]Wakabayashi K, Tanji K, Odagiri S, et al. The Lewy body in Parkinson’s disease and related neurodegenerative disorders. Molecular neurobiology. 2013; 47(2): 495-508.

[8]Shahmoradian SH, Lewis AJ, Genoud C, et al. Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nature neuroscience. 2019; 22(7): 1099-1109.

[9]Ubeda-Banon I, Saiz-Sanchez D, de la Rosa-Prieto C, et al. α-Synucleinopathy in the human olfactory system in Parkinson’s disease: involvement of calcium-binding protein-and substance P-positive cells. Acta neuropathologica. 2010; 119(6): 723-735.

[10]Langston JW, Forno LS. The hypothalamus in Parkinson disease. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 1978; 3(2): 129-133.

[11]Homma T, Mochizuki Y, Mizutani T. Phosphorylated α‐synuclein immunoreactivity in the posterior pituitary lobe. Neuropathology. 2012; 32(4): 385-389.

[12]Braak H, Rueb U, Sandmann-Keil D, et al. Parkinson’s disease: affection of brain stem nuclei controlling premotor and motor neurons of the somatomotor system. Acta neuropathologica. 2000; 99(5): 489-495.

[13]Mori F, Piao Y-S, Hayashi S, et al. α-Synuclein accumulates in Purkinje cells in Lewy body disease but not in multiple system atrophy. Journal of Neuropathology & Experimental Neurology. 2003;62(8):812-819.

[14]Braak H, Sastre M, Bohl JR, de Vos RA, et al. Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre-and postganglionic neurons. Acta neuropathologica. 2007; 113(4): 421-429.

[15]Tamura T, Yoshida M, Hashizume Y, et al. Lewy body‐related α‐synucleinopathy in the spinal cord of cases with incidental Lewy body disease. Neuropathology. 2012; 32(1): 13-22.

[16]Braak H, Braak E, Yilmazer D, et al. Amygdala pathology in Parkinson’s disease. Acta neuropathologica. 1994; 88(6): 493-500.

[17]Wakabayashi K, Hansen LA, Masliah E. Cortical Lewy body-containing neurons are pyramidal cells: laser confocal imaging of double-immunolabeled sections with anti-ubiquitin and SMI32. Acta neuropathologica. 1995; 89(5): 404-408.

[18]Forno LS, Norville RL. Ultrastructure of Lewy bodies in the stellate ganglion. Acta neuropathologica. 1976; 34(3): 183-197.

[19]Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric α-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neuroscience letters. 2006; 396(1): 67-72.

[20]Kuo Y-M, Li Z, Jiao Y, et al. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-synuclein gene mutations precede central nervous system changes. Human molecular genetics. 2010; 19(9): 1633-1650.

[21]Mrabet S, Ben Ali N, Achouri A, et al. Gastrointestinal dysfunction and neuropathologic correlations in Parkinson disease. Journal of clinical gastroenterology. 2016; 50(9): e85-e90.

[22]Stokholm MG, Danielsen EH, Hamilton‐Dutoit SJ, et al. Pathological α‐synuclein in gastrointestinal tissues from prodromal P arkinson disease patients. Annals of neurology. 2016; 79(6): 940-949.

[23]Orimo S, Uchihara T, Nakamura A, et al. Axonal α-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson’s disease. Brain. 2008; 131(3): 642-650.

[24]Minguez-Castellanos A, Chamorro C, Escamilla-Sevilla F, et al. Do α-synuclein aggregates in autonomic plexuses predate Lewy body disorders?: a cohort study. Neurology. 2007; 68(23): 2012-2018.

[25]Fumimura Y, Ikemura M, Saito Y, et al. Analysis of the adrenal gland is useful for evaluating pathology of the peripheral autonomic nervous system in Lewy body disease. Journal of neuropathology and experimental neurology. 2007; 66(5): 354-362.

[26]Del Tredici K, Hawkes CH, Ghebremedhin E, et al. Lewy pathology in the submandibular gland of individuals with incidental Lewy body disease and sporadic Parkinson’s disease. Acta neuropathologica. 2010; 119(6): 703-713.

[27]Vilas D, Iranzo A, Tolosa E, et al. Assessment of α-synuclein in submandibular glands of patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study. The Lancet Neurology. 2016; 15(7): 708-718.

[28]Miki Y, Tomiyama M, Ueno T, et al. Clinical availability of skin biopsy in the diagnosis of Parkinson’s disease. Neuroscience letters. 2010; 469(3): 357-359.

[29]Donadio V, Incensi A, Leta V, et al. Skin nerve α-synuclein deposits A biomarker for idiopathic Parkinson disease. Neurology. 2014; 82(15): 1362-1369.

[30]George JM. The synucleins. Genome biology. 2001; 3(1): reviews3002. 3001.

[31]Surguchov A. Intracellular dynamics of synucleins:“here, there and everywhere”. In: International review of cell and molecular biology. Vol 320. Elsevier; 2015: 103-169.

[32]Lavedan C. The synuclein family. Genome research. 1998; 8(9): 871-880.

[33]Clayton DF, George JM. The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends in neurosciences. 1998; 21(6): 249-254.

[34]Kallman M. Synthesis and Evaluation of α-Synuclein (6-36). 2013.

[35]Shen J, Du T, Wang X, et al. α-Synuclein amino terminus regulates mitochondrial membrane permeability. Brain research. 2014; 1591: 14-26.

[36]Liu Y, Qiang M, Wei Y, et al. A novel molecular mechanism for nitrated α-synuclein-induced cell death. Journal of molecular cell biology. 2011; 3(4): 239-249.

[37]Dettmer U, Selkoe D, Bartels T. New insights into cellular α-synuclein homeostasis in health and disease. Current opinion in neurobiology. 2016; 36: 15-22.

[38]Emamzadeh FN. Alpha-synuclein structure, functions, and interactions. Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences. 2016; 21.

[39]Galvin JE, Schuck TM, Lee VM-Y, et al. Differential expression and distribution of α-, β-, and γ-synuclein in the developing human substantia nigra. Experimental neurology. 2001; 168(2): 347-355.

[40]Surguchov A. Molecular and cellular biology of synucleins. International review of cell and molecular biology. 2008; 270: 225-317.

[41]Nam M-K, Han J-H, Jang J-Y, et al. A novel link between the conformations, exposure of specific epitopes, and subcellular localization of α-synuclein. Biochimica et Biophysica Acta (BBA)-General Subjects. 2015; 1850(12): 2497-2505.

[42]Sui Y-T, Bullock KM, Erickson MA, Zet al.. Alpha synuclein is transported into and out of the brain by the blood–brain barrier. Peptides. 2014; 62: 197-202.

[43]Marmolino D, Foerch P, Atienzar F, et al. Alpha synuclein dimers and oligomers are increased in overexpressing conditions in vitro and in vivo. Molecular and Cellular Neuroscience. 2016; 71: 92-101.

[44]DeMaagd G, Philip A. Parkinson’s Disease and Its Management: Part 1: Disease Entity, Risk Factors, Pathophysiology, Clinical Presentation, and Diagnosis. Pharmacy and Therapeutics. 2015; 40(8): 504.

[45]Luna E, Luk KC. Bent out of shape: α-Synuclein misfolding and the convergence of pathogenic pathways in Parkinson’s disease. FEBS letters. 2015; 589(24): 3749-3759.

[46]Surguchev A, Surguchov A. Effect of α‐synuclein on membrane permeability and synaptic transmission: a clue to neurodegeneration? Journal of neurochemistry. 2015; 132(6): 619-621.

[47]Winner B, Jappelli R, Maji SK, et al. In vivo demonstration that α-synuclein oligomers are toxic. Proceedings of the National Academy of Sciences. 2011; 108(10): 4194-4199.

[48]Oueslati A, Fournier M, Lashuel HA. Role of post-translational modifications in modulating the structure, function and toxicity of α-synuclein: implications for Parkinson’s disease pathogenesis and therapies. In: Progress in brain research. Vol 183. Elsevier; 2010: 115-145.

[49]Liu C, Fei E, Jia N, et al. Assembly of lysine 63-linked ubiquitin conjugates by phosphorylated α-synuclein implies Lewy body biogenesis. Journal of Biological Chemistry. 2007; 282(19): 14558-14566.

[50]McKinnon C, Tabrizi SJ. The ubiquitin-proteasome system in neurodegeneration. Antioxidants & redox signaling. 2014; 21(17): 2302-2321.

[51]Zheng Q, Huang T, Zhang L, et al. Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases. Frontiers in aging neuroscience. 2016; 8: 303.

[52]Hernandez SM, Tikhonova EB, Karamyshev AL. Protein-Protein Interactions in Alpha-Synuclein Biogenesis: New Potential Targets in Parkinson’s Disease. Frontiers in Aging Neuroscience. 2020; 12: 72.

[53]Liu J, Li T, Thomas JM, et al. Synphilin-1 attenuates mutant LRRK2-induced neurodegeneration in Parkinson’s disease models. Human molecular genetics. 2016; 25(4): 672-680.

[54]Shishido T, Nagano Y, Araki M, et al. Synphilin-1 has neuroprotective effects on MPP+-induced Parkinson’s disease model cells by inhibiting ROS production and apoptosis. Neuroscience letters. 2019; 690: 145-150.

[55]Alim MA, Hossain MS, Arima K, et al. Tubulin seeds α-synuclein fibril formation. Journal of Biological Chemistry. 2002; 277(3): 2112-2117.

[56]Zhou R, Huang Y, Li X, et al. Molecular interaction of α-synuclein with tubulin influences on the polymerization of microtubule in vitro and structure of microtubule in cells. Molecular biology reports. 2010; 37(7): 3183-3192.

[57]Chandra S, Gallardo G, Fernández-Chacón R,et al. α-Synuclein cooperates with CSPα in preventing neurodegeneration. Cell. 2005; 123(3): 383-396.

[58]Burgoyne RD, Morgan A. Cysteine string protein (CSP) and its role in preventing neurodegeneration. Paper presented at: Seminars in cell & developmental biology2015.

[59]Shi M-m, Shi C-h, Xu Y-m. Rab GTPases: the key players in the molecular pathway of Parkinson’s disease. Frontiers in cellular neuroscience. 2017; 11: 81.

[60]Volpicelli-Daley LA. Effects of α-synuclein on axonal transport. Neurobiology of disease. 2017; 105: 321-327.

[61]Liu I-H, Uversky VN, Munishkina LA, et al. Agrin binds α-synuclein and modulates α-synuclein fibrillation. Glycobiology. 2005; 15(12): 1320-1331.

[62]Uversky VN, Eliezer D. Biophysics of Parkinson’s disease: structure and aggregation of α-synuclein. Current Protein and Peptide Science. 2009; 10(5): 483-499.

[63]Candelise N, Schmitz M, Thüne K, et al. Effect of the micro-environment on α-synuclein conversion and implication in seeded conversion assays. Translational Neurodegeneration. 2020; 9(1): 1-16.

[64]Jiang P, Gan M, Yen S-H, et al. Histones facilitate α-synuclein aggregation during neuronal apoptosis. Acta neuropathologica. 2017; 133(4): 547-558.

[65]Burmann BM, Gerez JA, Matečko-Burmann I, et al. Regulation of α-synuclein by chaperones in mammalian cells. Nature. 2020; 577(7788): 127-132.

[66]Wang B, Underwood R, Kamath A, et al. 14-3-3 Proteins Reduce Cell-to-Cell Transfer and Propagation of Pathogenic α-Synuclein. Journal of Neuroscience. 2018; 38(38): 8211-8232.

[67]Ishizawa T, Mattila P, Davies P, et al. Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. Journal of Neuropathology & Experimental Neurology. 2003; 62(4): 389-397.

[68]Moussaud S, Jones DR, Moussaud-Lamodière EL, et al. Alpha-synuclein and tau: teammates in neurodegeneration? Molecular neurodegeneration. 2014; 9(1): 43.

[69]Fusco G, Chen SW, Williamson PT, et al. Structural basis of membrane disruption and cellular toxicity by α-synuclein oligomers. Science. 2017; 358(6369): 1440-1443.

[70]Burré J, Sharma M, Südhof TC. Cell biology and pathophysiology of α-synuclein. Cold Spring Harbor perspectives in medicine. 2018; 8(3): a024091.

[71]Hegde ML, Rao K. DNA induces folding in α-synuclein: understanding the mechanism using chaperone property of osmolytes. Archives of biochemistry and biophysics. 2007; 464(1): 57-69.

[72]Vasudevaraju P, Guerrero E, Hegde ML, et al. New evidence on α-synuclein and Tau binding to conformation and sequence specific GC* rich DNA: relevance to neurological disorders. Journal of pharmacy & bioallied sciences. 2012; 4(2): 112.

[73]Ni H-M, Williams JA, Ding W-X. Mitochondrial dynamics and mitochondrial quality control. Redox biology. 2015; 4: 6-13.

[74]Nakamura K. α-Synuclein and mitochondria: partners in crime? Neurotherapeutics. 2013; 10(3): 391-399.

[75]Di Maio R, Barrett PJ, Hoffman EK, et al. α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Science translational medicine. 2016; 8(342): 342ra78.

[76]Exner N, Lutz AK, Haass C, et al. Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. The EMBO journal. 2012; 31(14): 3038-3062.

[77]Jin H, Kanthasamy A, Ghosh A, et al. α-Synuclein negatively regulates protein kinase Cδ expression to suppress apoptosis in dopaminergic neurons by reducing p300 histone acetyltransferase activity. Journal of Neuroscience. 2011; 31(6): 2035-2051.

[78]Hashimoto M, Hsu LJ, Rockenstein E, Tet al. α-Synuclein protects against oxidative stress via inactivation of the c-Jun N-terminal kinase stress-signaling pathway in neuronal cells. Journal of Biological Chemistry. 2002; 277(13): 11465-11472.

[79]Oaks AW, Sidhu A. Parallel mechanisms for direct and indirect membrane protein trafficking by synucleins. Communicative & integrative biology. 2013; 6(6): e26794.

[80]Südhof TC. The synaptic vesicle cycle. Annu Rev Neurosci. 2004; 27: 509-547.

[81]Rizo J, Südhof TC. The membrane fusion enigma: SNAREs, Sec1/Munc18 proteins, and their accomplices—guilty as charged? Annual review of cell and developmental biology. 2012; 28: 279-308.

[82]Vargas KJ, Makani S, Davis T, et al. Synucleins regulate the kinetics of synaptic vesicle endocytosis. Journal of Neuroscience. 2014; 34(28): 9364-9376.

[83]Gorbatyuk OS, Li S, Nguyen FN, et al. α-Synuclein expression in rat substantia nigra suppresses phospholipase D2 toxicity and nigral neurodegeneration. Molecular Therapy. 2010; 18(10): 1758-1768.

[84]Venda LL, Cragg SJ, Buchman VL, et al. α-Synuclein and dopamine at the crossroads of Parkinson’s disease. Trends in neurosciences. 2010; 33(12): 559-568.

[85]Bendor JT, Logan TP, Edwards RH. The function of α-synuclein. Neuron. 2013; 79(6): 1044-1066.

[86]Mao X, Ou MT, Karuppagounder SS, et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016; 353(6307): aah3374.

[87]Masuda-Suzukake M, Nonaka T, Hosokawa M, et al. Prion-like spreading of pathological α-synuclein in brain. Brain. 2013; 136(4): 1128-1138.

[88]Chistiakov DA, Chistiakov AA. α-Synuclein-carrying extracellular vesicles in Parkinson’s disease: deadly transmitters. Acta Neurologica Belgica. 2017; 117(1): 43-51.

[89]Codolo G, Plotegher N, Pozzobon T, et al. Triggering of Inflammasome by Aggregated α–Synuclein, an Inflammatory Response in Synucleinopathies. PloS one. 2013; 8(1): e55375.

[90]Dzamko N, Gysbers A, Perera G, et al. Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology. Acta neuropathologica. 2017; 133(2): 303-319.

[91]Béraud D, Hathaway HA, Trecki J, et al. Microglial activation and antioxidant responses induced by the Parkinson’s disease protein α-synuclein. Journal of Neuroimmune Pharmacology. 2013; 8(1): 94-117.

[92]Prajapati P, Sripada L, Singh K, et al. TNF-α regulates miRNA targeting mitochondrial complex-I and induces cell death in dopaminergic cells. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2015; 1852(3): 451-461.