Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
To purchase hard copies of this book, please contact the representative in India:
CBS Publishers & Distributors Pvt. Ltd.
www.cbspd.com
|
customercare@cbspd.com
Parkinson’s disease (PD) is a neurodegenerative disorder affecting the motor system and occurring in the central nervous system. One of the symptoms of PD is accumulation of Lewy bodies and Lewy neurites. The alpha-synuclein (SNCA) gene is part of the protein complex called Lewy body. The SNCA gene encoding a presynaptic protein product is thought to play a role in PD-related important pathways. It is suggested that there is a relationship between the risk of PD development and SNCA levels, and it is suggested that SNCA level is an important marker in PD diagnosis. Various polymorphisms have been identified in the 5′ and/or 3′ UTR regions of the SNCA gene, and as a result of these polymorphisms, changes occur in the binding of transcription factors. The identification of the roles of SNCA gene polymorphisms in PD development may enable the development of new methods for the treatment of PD.
Department of Biophysics, Faculty of Medicine, T.C. Halic University, Turkey
Arzu Ay
Department of Biophysics, Faculty of Medicine, Trakya University, Turkey
*Address all correspondence to: nevraalkanli@halic.edu.tr
1. Introduction
The most important feature of age-related neurodegenerative diseases is the slow and irreversible deterioration of brain function. PD affects the motor system and is a neurodegenerative disorder of the central nervous system [1]. The prevalence of PD, which is known to be the second progressive neurodegenerative disease, increases with age. PD, which causes severe morbidity, has motor symptoms such as tremors, bradykinesia, muscle stiffness, and postural instability and non-motor symptoms, i.e., autonomic dysfunction, sensory symptoms, sleep disturbances, and fatigue. These symptoms occur as a result of the progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta, clustering of proteins within the brain, Lewy bodies, and Lewy neurites [2, 3]. As a result of degeneration of dopaminergic neurons, movement disorder occurs, and the cause of this movement disorder is the neurotransmitter dopamine deficiency. Although the basic mechanism of neuronal death in PD is unknown, genetic and environmental factors have been found to be effective in the pathogenesis of the disease [4].
It has been reported that many genes play a role in the pathogenesis of PD, and polymorphisms in these genes may be genetic risk factors for PD development [5]. A large number of different DNA variants have been identified in disease genes associated with familial PD in molecular genetic analyses. These genetic variants include SNCA, Parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), DJ-1 (PARK7), and leucine-rich repeat kinase 2 (LRRK2) variants [6].
The SNCA gene plays a role in important pathways associated with PD. It is suggested that there is a significant relationship between SNCA levels and the risk of PD development, and SNCA levels are thought to be an important marker in the diagnosis of PD. Several studies have been conducted to explain the relationship between genetic polymorphisms in different regions of the SNCA gene and risk of PD [7].
Polymorphisms that occur in different regions of the SNCA gene, an important gene for PD etiology, have been identified in relation to PD [7, 8]. Changes in SNCA expression levels are one of the main mechanisms of SNCA to cause PD [7, 9, 10]. As a result of polymorphisms in the 5′ and 3′ UTR regions of the SNCA gene, the binding of transcription factors and miRNAs can be altered, and promoter activity is affected. Thus, gene expression can be regulated. According to the general results from the studies aimed to investigate the relationship between SNCA gene polymorphisms and the risk of PD development, the SNCA gene and some polymorphisms of this gene have been identified as genetic risk factors in PD development [7].
The purpose of this chapter is, in addition to giving general information about PD, to summarize the studies that investigated on the relationship between SNCA gene polymorphisms and the risk of developing PD.
Parkinson’s disease (PD), the second most common neurodegenerative disease after Alzheimer’s disease, affects approximately 1–2% of individuals over 65 years of age [11, 12]. The incidence of PD usually begins after 50 years of age and increases more after 60 years of age [13]. The prevalence of PD increases approximately 4% in people over 85 years of age [6]. PD is a neurological disorder associated with increased morbidity and reduced survival [14, 15].
PD is characterized by bradykinesia, resting tremor, rigidity, and postural instability. PD is associated with the formation of Lewy bodies [16]. Lewy bodies of postmortem that are determined in brain autopsy specimens are the distinguishing features of PD. These bodies are observed in intense eosinophilic nuclei and cytoplasmic inclusions. The presence of intraneuronal protein inclusions, called Lewy bodies or Lewy neurites, is one of the neuropathological features of PD [17].
In PD, in addition to motor symptoms, non-motor symptoms occur. Motor symptoms in PD are due to the selective loss of dopaminergic neurons in the midbrain and the axon terminals reflected in the dorsal striatum [18]. Motor symptoms occur when neuronal cell loss reaches 80% or more as a result of progressive loss in the dopaminergic neurons of substantia nigra pars compacta [19]. Non-motor symptoms of PD are autonomic dysfunction and cognitive impairment [20]. The motor and non-motor symptoms of PD are caused by the loss of the dopaminergic neurons of the substantia nigra [21, 22, 23]. PD is defined as a syndrome because it is a complex disease characterized by motor and non-motor symptoms [20].
The majority of PD cases are sporadic cases; however, it is known that 10–15% are familial cases, and the majority of these cases are hereditary. Environmental and genetic factors play a role together in the pathogenesis of PD, which has a complex etiology [24].
SNCA protein is the major protein of Lewy bodies. This protein is a presynaptic phosphoprotein that has a specific tendency to aggregation that plays an important role in both hereditary and idiopathic PD [25]. SNCA protein and fibrils constitute Lewy bodies [16]. In Lewy bodies, SNCA protein is predominant and is therefore known to be associated with the etiology of PD. SNCA also has an important function in the pathological process of PD [26, 27]. SNCA, an important component of Lewy bodies, is one of the distinctive features of PD [28, 29, 30].
The SNCA protein, which contains 144 amino acids, found as a soluble protein, not naturally folded in the cytoplasm, is encoded by three different SNCA transcripts. The function of the SNCA protein in the brain is still not fully elucidated, but it has been found to play an important role in the neurotransmitter release and vesicle cycle at presynaptic terminals [6]. SNCA plays an important role in the regulation of neurotransmitter release, synaptic function, and plasticity of dopaminergic neurons [31, 32, 33].
Dopamine from presynaptic vesicles plays an important role in the normal functioning of a presynaptic complex [34, 35, 36]. Function of the SNCA protein, which is highly expressed in the brain; is the vesicle formation required for storage and transport of dopamine. Dopamine transported from the presynaptic neuron to the postsynaptic neuron is important for smooth and coordinated movements of the body. As a result of mutations in the SNCA protein, the vesicle that required for the dopamine transport cannot form, and the aggregates are formed. These aggregates are identified as important distinguishing features in PD pathogenesis. Genetic changes known to be effective in PD pathogenesis disrupt normal function of SNCA protein [37, 38].
The SNCA gene is localized on the fourth chromosome in the human genome. It is the first gene associated with PD that contains a pathogenic missense mutation (Ala53Thr) responsible for the disease in a large Italian family [6]. The SNCA gene plays a role in important pathways associated with PD and encodes the presynaptic protein product. Therefore, this gene is one of the genes that are extensively studied among PD susceptibility genes [39].
It is the first causal gene in familial PD, and it encodes SNCA with main component of Lewy bodies. Lewy bodies accumulate in neural cells in familial PD cases. The reason of this accumulation is overproduction of SNCA. Overproduction of normal SNCA also plays an important role in the pathogenesis of sporadic PD [40].
The chromosomal location is presented in Figure 1.
Genetic predisposition plays an important role in the etiology of PD. Multiple linkage and genome-wide association studies (GWAS) were performed to determine genetic polymorphisms in the SNCA gene. Single-nucleotide gene polymorphisms in the SNCA gene were found to be associated with increased PD risk. Single-nucleotide polymorphisms in the SNCA gene can lead to a change in PD susceptibility, resulting in increased or decreased PD risk. Several genes and several polymorphisms of the SNCA gene have been identified in GWAS. It has been determined that some of these gene polymorphisms may be important risk factors especially for sporadic PD [26]. Polymorphisms in different regions of the SNCA gene have been studied in various studies with different populations [7]. Genetic risk factors are very important in the development of PD, and up to now, 16 loci have been identified, which are known to be associated with the development of PD. Very few of the PD, which is mostly sporadic, are familial. The cause of familial PD development is autosomal recessive or dominant mutations. In particular, mutagenic mutations (SNCA, LRRK2, PRKN, DJ-1, and PINK1) occurring in five genes were found to be related to familial PD. Six loci such as MAPT, SNCA, HLA-DRBS, BST1, GAK, and LRRK2, which are associated with sporadic PD, are also defined. In a meta-analysis of various GWAS studies, five new loci identified to be associated with idiopathic PD were identified. ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R loci are found among these loci [20]. SNCA mutations contribute to PD development as a result of amino acid displacements and configuration changes in the encoded protein [41, 42].
Mata et al. found that SNCA gene polymorphisms were important risk factors for PD development risk. In a study conducted by Mata et al., a significant relationship was found between SNCA plasma levels and rs356219 single-nucleotide gene polymorphism [43]. In a study conducted with the Korean population, it was determined that the G allele of rs356219 gene polymorphism was associated with the risk of PD development [44]. In studies conducted with populations of North America, Spain, Russia, and China, rs356219 gene polymorphism was identified as a genetic risk factor for PD development risk [26].
In several families of Greek origin and in families of Asian, Swedish, and Polish origins, p.Ala53Thr polymorphism, one of the rare mutations in the SNCA gene, was detected [6].
In a study that performed to investigate the relationship between rs2301134, rs2301135, rs356221, and rs11931074 gene polymorphisms and PD development risk, the significant relationship was determined between two promoter polymorphisms of the SNCA gene (rs2301134 and rs2301135 gene polymorphisms) and PD development risk. In this study, genotype frequencies in rs11931074 gene polymorphism in 3′ UTR region of SNCA gene were found to be significantly different in patient and control groups. In this study conducted with the Iranian population, SNCA gene polymorphisms were identified as a genetic risk factor in PD development. In another study, the relationships between the rs2301134, rs2301135, rs11931074, and rs356221 gene polymorphisms and the risk of PD development were determined in the SNCA gene. In this study, CC genotype and C allele of rs2301134 gene polymorphism were found to be related to increased PD risk. In addition, CC genotype and C allele of rs2301135 gene polymorphism and GG genotype of rs11931074 gene polymorphism were determined to be associated with decreased PD [6]. In another study conducted with the Han-Chinese population, rs2301135 gene polymorphism was found to be an important risk factor for sporadic PD development. However, rs356221 gene polymorphism was not effective in PD development [45]. Mata et al. also found that SNCA gene polymorphisms were important risk factors for PD development risk [43]. A meta-analysis study to determine 10 candidate single-nucleotide polymorphisms of the SNCA gene showed a significant relationship between rs11931074 gene polymorphism and PD development risk [28]. In a study conducted in the United States, it was found that some single-nucleotide gene polymorphisms in the SNCA gene were associated with the risk of PD development, but no significant relationship was determined between rs11931074 gene polymorphism and PD development risk [46]. In a study conducted with a South American Brazilian population, the relationship between rs2583988, rs356219, rs2736990, and rs11931074 gene polymorphisms and the risk of PD development was investigated, and the significant relationship was determined between rs356219 gene polymorphism and increased cognitive disorder in PD patients [13]. In studies conducted with European and North American populations, rs2736990 gene polymorphism has been identified as a genetic risk factor in PD development [47]. In another study conducted with a Chinese population, a significant relationship was found between the T allele of the rs11931074 polymorphism of the SNCA gene and the G allele and PD risk of the rs894278 polymorphism. G allele of gene polymorphism of rs11931074 was found associated with decreased progression PD risk [29]. Primer sequences for rs2301134, rs2301135, rs356221, and rs11931074 gene polymorphisms are presented in Table 1 [7].
In a study conducted by Yu et al. with Han-Chinese population, a significant relationship was found between the risk of PD development and the polymorphism of rs7684318, which is the intronic polymorphism of the SNCA gene [48].
Rep 1, a complex microsatellite repeat of about 10 kilobases in length, is located in the translation start region of the SNCA gene. In some studies, a significant relationship was found between specific SNCA-Rep 1 alleles and the risk of late onset idiopathic PD development. However, there are also studies indicating that Rep 1 risk alleles are not a genetic risk factor for the development of idiopathic PD or that these risk alleles and PD development are inversely related [49]. Rep 1 polymorphic microsatellite repeat is localized in the promoter region (above 10 kb the transcription start site) of the SNCA gene [49]. Rep 1–261 is a microsatellite polymorphic variant associated with an increase in SNCA mRNA levels [47]. There are two common Rep 1 alleles as 251 and 261 bp in length, and functional assays about these alleles were performed. According to these functional analyses, while a significant relationship was found between the risky allele with a length of 261 bp and the upregulation of SNCA gene expression, a significant relationship was found between protective variant 259 bp length and decreased SNCA gene expression [49]. In addition, variability in the length of the Rep 1 repeat sequence is associated with PD susceptibility. Genotypes containing 263 bp allele of this sequence were associated with increased risk of PD development, and genotypes containing 259 bp allele were associated with decreased risk of PD development [42]. Changes in the promoter region and genetic variations in 30 untranslated SNCA gene regions have been associated with susceptibility to PD [49]. In the SNCA promoter (SNCA-Rep 1), it was determined that the localized Rep 1 and 3′ untranslated region polymorphisms interfered with the transcription binding regions and played an important role in increasing PD susceptibility. Thus, target regions of miRNAs that alter SNCA gene expression are formed or disappear [26]. The significant difference was determined between Rep 1–259 allele and low levels of SNCA mRNA in postmortem brain tissues of patients with PD. Rep 1 microsatellite repeat and rs2583988, rs2619363, rs2619364 gene polymorphisms were found to be a relationship between. In a study conducted with a population selected from Belgium, Germany, and Serbia, the relationship was found between Rep 1 microsatellite repeat; rs2583988, rs2619363, and rs2619364 gene polymorphisms; and PD. In a study conducted with German and Japanese populations, it was observed that there was a link between intron 4 and 5′ and 3′ untranslated regions (UTRs) in the SNCA gene [6]. In a Russian population study, TT genotype of rs2583988 and rs2619363 gene polymorphisms and the GG genotype of rs2619364 gene polymorphism were found to be associated with higher levels of SNCA mRNA [47]. There are many small-scale studies aimed at investigating this relationship, and also, in a meta-analysis study conducted by Maraganore et al., in a large population selected from 11 different regions, the relationship between the rep 1 gene polymorphism and the risk of PD development has been proven [42].
In an analysis with the Caucasus population to investigate the relationship between 12 single-nucleotide polymorphisms and PD, including the whole SNCA gene region, it was determined that signals were collected in a 24 kb-long region in the middle of intron 4 of the SNCA gene, and it was determined that these signals were confirmed by haplotype analysis showing the presence of a strong protective allele [42].
In addition to these gene polymorphisms, SNCA gene polymorphisms which are known to be associated with PD include rs104893875 (G > A), rs104893877 (G > A), and rs104893878 (G > C) gene polymorphisms. It has been reported that the polymorphism rs104893875 (G > A) has been identified primarily in a multinational Spanish family. The significant relationship was determined between rs104893875 (G > A) gene polymorphism and increased SNCA protein aggregation. In another study conducted with the Swedish population, as a result of rs104893877 (G > A) mutation, PD and encephalopathy with cortical involvement develop. Immunoreactive Lewy neurites were detected in brain stem pigmented nuclei, the hippocampus, and temporal neocortexes of PD patients in whom this gene polymorphism was detected. In a study that is significant relationship between rs104893878 (G > C) gene polymorphism and autosomal dominant PD, hypometabolism was determined in frontal, parietal, and left temporal cortexes of PD patients in whom this polymorphism was detected. As a result of postmortem examination of brain slices of these patients, Lewy bodies and neurodegeneration developed and correspondingly identified. Primer sequences for rs104893875 (G/A), rs104893877 (G > A), and rs104893878 (G > C) gene polymorphisms are presented in Table 2 [38].
There are three missense mutations, A53T, A30P, and E46K, as the most common pathogenic changes of the SNCA gene. In a study conducted with the Mexican Mestizos population, a significant relationship was determined between the rs1801133 and rs3857059 allelic variations of the SNCA gene and the risk of PD development. In addition, GG genotype of rs3857059 gene polymorphism was found to be a genetic risk factor for PD development [50]. While A18T and A29S missense mutations in patients with sporadic PD; A53T, A30P, E46K, and H50Q missense mutations in familial PD patients have been described. Dual and triple copies of the SNCA locus known to be associated with PD severity cause familial Parkinsonism [26].
There are studies showing that there are significant relationships between some polymorphisms in the SNCA gene and the risk of sporadic PD development. It is also known that these polymorphisms are associated with increased levels of plasmatic SNCA. Tyrosine hydroxylase activity and dopamine release decrease as a result of SNCA overexpression. In order to investigate the relationship between SNCA gene polymorphisms and the risk of PD development, different results have been obtained in studies performed with different populations [13].
It is known that environmental and genetic factors play a role together in PD pathogenesis. Several studies have been carried out to investigate the relationship between gene polymorphisms and PD development risk, which are important among genetic factors, and different results have been obtained in these studies. It is thought that the differences in the results of these studies are due to of PD patient and healthy control groups’ different selection criteria and different race and populations. The identification of genetic polymorphisms that play an important role in the development of PD will enable us to have knowledge about the mechanism of PD. In addition, new treatment methods can be improved in order to prevent PD. By increasing the number of PD patients and healthy controls, different results can be obtained in studies with larger populations. As a result, in studies aimed at the relationship between SNCA gene polymorphisms and the risk of PD development, some of the SNCA gene polymorphisms were found to be genetic risk factors for PD development and play an important role in the pathogenesis of the disease.
This chapter was performed by Nevra Alkanli and Arzu Ay in Department of Biophysics, T.C. Halic University Medical Faculty and Department of Biophysics, Trakya University Medical Faculty.
We declare that there is no conflict of interest with any financial organization regarding the material discussed in the chapter.
References
1.Cilingir O, Ozkan S, Aras BD, et al. Association of functional RAGE gene polymorphisms with Parkinson’s disease in a Turkish cohort. Biomedical Research. 2017;28(19):8454-8460
2.Weikang C, Jie L, Likang L, et al. A meta-analysis of association between glutathione S-transferase M1 gene polymorphism and Parkinson’s disease susceptibility. Open Medicine. 2016;11:578-583
3.Emamzadeh FN, Surguchov A. Parkinson’s disease: Biomarkers, treatment, and risk factors. Frontiers in Neuroscience. 2018;12:612 https://doi.org/10.3389/fnins.2018.00612
4.Borlak J, Reamon-Buettner SM. N-acetyltransferase 2 (NAT2) gene polymorphisms in Parkinson’s disease. BMC Medical Genetics. 2006;7:30. DOI: 10.1186/1471-2350-7-30
5.Niu MY, Wang L, Xie AM. ApaI, BsmI, FokI, and TaqI polymorphisms in the vitamin D receptor gene and Parkinson’s disease. Chinese Medical Journal. 2015;128:1809-1814
6.Nuytemans K, Theuns J, Cruts M, et al. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: A mutation update. Human Mutation. 2010;31(7):763-780. DOI: 10.1002/humu.21277
7.Rahimi M, Akbari M, Jamshidi J, et al. Genetic analysis of SNCA gene polymorphisms in Parkinson’s disease in an Iranian population. Basal Ganglia. 2017;10:4-7. DOI: 10.1016/j.baga.2017.08.001
8.Spencer CCA, Plagnol V, Strange A, et al. Dissection of the genetics of Parkinson’s disease identifies an additional association 5′ of SNCA and multiple associated haplotypes at 17q21. Human Molecular Genetics. 2011;20(2):345-353. DOI: 10.1093/hmg/ddq469
9.Wu-Chou YH, Chen YT, Yeh TH, et al. Genetic variants of SNCA and LRRK2 genes are associated with sporadic PD susceptibility: A replication study in a Taiwanese cohort. Parkinsonism & Related Disorders. 2013;19(2):251-255. DOI: 10.1016/j.parkreldis.2012.10.019
10.Westerlund M, Belin AC, Anvret A, et al. Cerebellar alpha-synuclein levels are decreased in Parkinson’s disease and do not correlate with SNCA polymorphisms associated with disease in a Swedish material. The FASEB Journal. 2008;22(10):3509-3514. DOI: 10.1096/fj.08-110148
11.Bertram L, Tanzi RE. The genetic epidemiology of neurodegenerative disease. The Journal of Clinical Investigation. 2005;115(6):1449-1457. DOI: 10.1172/JCI24761
12.Jamshidi J, Movafagh A, Emamalizadeh B, et al. HLA-DRA is associated with Parkinson’s disease in Iranian population. International Journal of Immunogenetics. 2014;41(6):508-511. DOI: 10.1111/iji.12151
13.Campêlo CLC, Cagni FC, Figueredo D de S, et al. Variants in SNCA gene are associated with Parkinson’s disease risk and cognitive symptoms in a Brazilian sample. Frontiers in Aging Neuroscience. 2017;9:198. DOI: 10.3389/fnagi.2017.00198
14.Zambrino CA, Zorzi G, Lanzi G, et al. Influence of strict, intermediate, and broad diagnostic criteria on the age- and sex-specific incidence of Parkinson’s disease. Movement Disorders. 2000;15:819-825. DOI: 10.1002 2/1531-8257(200009)15:5<819::AID-MDS1009>3.0.CO;2-P
15.Elbaz A, Bower JH, Peterson BJ, et al. Survival study of Parkinson disease in Olmsted County, Minnesota. Archives of Neurology. 2003;60:91-96. DOI: 10.1001/archneur.60.1.91
16.Braak H, Del Tredici K, Rüb U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging. 2003;24:197-211. DOI: 10.1016/S0197-4580(02)00065-9
17.Spillantini MG, Schmidt ML, Lee VMY, et al. α-Synuclein in Lewy bodies. Nature. 1997;388(6645):839-840. DOI: 10.1007/s11172-007-0336-1
18.Hornykiewicz O. Dopamin (3-Hydroxytyramin) im Zentralnervensystem und seine Beziehung zum Parkinson-Syndrom des Menschen. Deutsche Medizinische Wochenschrift. 1962;87:1807-1810. DOI: 10.1055/s-0028-1114024
19.Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: Substantia nigra regional selectivity. Brain. 1991;114:2283-2201. DOI: 10.1093/brain/114.5.2283
20.Sassi C. Genetics of Parkinson disease. Intech Open. 2014;2:64
21.Searles Nielsen S, Bammler TK, Gallagher LG, et al. Genotype and age at Parkinson disease diagnosis. International Journal of Molecular Epidemiology and Genetics. 2013;4(1):61-69. DOI: 10.1108/IJCoMA-01-2013-0001
22.Haghnejad L, Emamalizadeh B, Jamshidi J, et al. Variation in the miRNA-433 binding site of FGF20 is a risk factor for Parkinson’s disease in Iranian population. Journal of the Neurological Sciences. 2015;355(1-2):72-74. DOI: 10.1016/j.jns.2015.05.020
23.Obeso JA, Rodriguez-Oroz MC, Goetz CG, et al. Missing pieces in the Parkinson’s disease puzzle. Nature Medicine. 2010;16(6):653-661. DOI: 10.1038/nm.2165
24.Klein C, Westenberger A. Genetics of Parkinson’s disease. Cold Spring Harb Perspectives in Medicine. 2012;2(1). DOI: 10.1101/cshperspect.a008888
25.Goedert M. Alpha-synuclein and neurodegenerative diseases. Nature Reviews. Neuroscience. 2001;2:492-501. DOI: 10.1038/35081564
26.Campêlo CLDC, Silva RH. Genetic variants in SNCA and the risk of sporadic Parkinson’s disease and clinical outcomes: A review. Parkinsons Disease. 2017;2017:4318416. DOI: 10.1155/2017/4318416
27.Surguchov A. Intracellular dynamics of synucleins: Here, there and everywhere. International Review of Cell and Molecular Biology. 2015;320:103-169
28.Han W, Liu Y, Mi Y, et al. Alpha-synuclein (SNCA) polymorphisms and susceptibility to Parkinson’s disease: A meta-analysis. American Journal of Medical Genetics Part B Neuropsychiatric Genetics. 2015; 168B(2)123-134. DOI: 10.1002/ajmg.b.32288
29.Liu J, Xiao Q, Wang Y, et al. Analysis of genome-wide association study-linked loci in Parkinson’s disease of mainland China. Movement Disorders. 2013;28(13):1892-1895. DOI: 10.1002/mds.25599
30.Chen W, Kang WY, Chen S, et al. Hyposmia correlates with SNCA variant and non-motor symptoms in Chinese patients with Parkinson’s disease. Parkinsonism & Related Disorders. 2015;21(6):610-614. DOI: 10.1016/j.parkreldis.2015.03.021
31.Lashuel HA, Overk CR, Oueslati A, et al. The many faces of α-synuclein: From structure and toxicity to therapeutic target. Nature Reviews. Neuroscience. 2013;14(1):38-48. DOI: 10.1038/nrn3406
32.Bendor JT, Logan TP, Edwards RH. The function of α-synuclein. Neuron. 2013;79(6):1044-1066. DOI: 10.1016/j.neuron.2013.09.004
33.Eisbach SE, Outeiro TF. Alpha-Synuclein and intracellular trafficking: Impact on the spreading of Parkinson’s disease pathology. Journal of Molecular Medicine. 2013;91(6):693-703. DOI: 10.1007/s00109-013-1038-9
34.Burré J, Sharma M, Tsetsenis T, et al. α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science. 2010;329(5999):1663-1667. DOI: 10.1126/science.1195227
35.Choi B-K, Choi M-G, Kim J-Y, et al. Large alpha-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking. Proceedings of the National Academy of Sciences. 2013;110(10):4087-4092. DOI: 10.1073/pnas.1218424110
36.McCarthy JJ, Linnertz C, Saucier L, et al. The effect of SNCA 3′ region on the levels of SNCA-112 splicing variant. Neurogenetics. 2011;12(1):59-64. DOI: 10.1007/s10048-010-0263-4
37.Pandey N, Schmidt RE, Galvin JE. The alpha-synuclein mutation E46K promotes aggregation in cultured cells. Experimental Neurology. 2006;197:515-520. DOI: 10.1016/j.expneurol.2005.10.019
38.Anwarullah, Sultan A, Usmani MA, et al. Absence of SNCA polymorphisms in Pakistani Parkinson’s disease patients. Journal of Pakistan Medical Association. 2017;67:1512
39.Bekris LM, Mata IF, Zabetian CP. The genetics of Parkinson disease. Journal of Geriatric Psychiatry and Neurology. Epub ahead of print 2010;23:228e42. DOI: 10.1177/0891988710383572
40.Lesage S, Brice A. Parkinson’s disease: From monogenic forms to genetic susceptibility factors. Human Molecular Genetics. 2009;18:R48e59. DOI: 10.1093/hmg/ddp012
41.SNCA Synuclein Alpha. Homo sapiens (human). HGNC:HGNC:11138
42.Maraganore DM, De Andrade M, Elbaz A, et al. Collaborative analysis of α-synuclein gene promoter variability and Parkinson disease. The Journal of the American Medical Association. 2006;296(6). DOI: 10.1001/jama.296.6.661
43.Mata IF, Shi M, Agarwal P, et al. SNCA variant associated with Parkinson disease and plasma α-synuclein level. Archives of Neurology. 2010;(11):1350-1356. DOI: 10.106701/archneurol.2010.279
44.Kim HJ, Kim JM, Lee JY, et al. α-Synuclein polymorphism and Parkinson’s disease in a tau homogeneous population. Neurology Asia. 2010;15(1):61-63
45.Fang J, Yi K, Guo M, et al. Analysis of LRRK2, SNCA, and ITGA8 gene variants with sporadic Parkinson’s disease susceptibility in Chinese Han population. Parkinsons Disease. 2016;2016:3474751. DOI: 10.1155/2016/3474751
46.Davis AA, Andruska KM, Benitez BA, et al. Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression. Neurobiology of Aging. 2016;37(209):e1-e7. DOI: 10.1016/j.neurobiolaging.2015.09.014
47.Alieva AK, Shadrina MI, Filatova EV, et al. Polymorphisms in the SNCA gene: Association with the risk of development of the sporadic form of Parkinson’s disease and the level of SNCA gene expression in peripheral blood of patients from Russia. Neuroscience Medicine. 2013;4:208-214
48.Yu L, Xu P, He X, et al. SNP rs7684318 of the α-synuclein gene is associated with Parkinson’s disease in the Han Chinese population. Brain Research. 2010;1346:262-265
49.Trotta L, Guella I, Soldà G, et al. SNCA and MAPT genes: Independent and joint effects in Parkinson disease in the Italian population. Parkinsonism & Related Disorders. 2012;18(3):257-262. DOI: 10.1016/j.parkreldis.2011.10.014
50.García S, Chavira-Hernández G, Gallegos-Arreola MP, et al. The rs3857059 variant of the SNCA gene is associated with Parkinson’s disease in Mexican mestizos. Arquivos de Neuro-Psiquiatria. 2016;74(6):445-449. DOI: 10.1590/0004-282X20160061
Written By
Nevra Alkanli and Arzu Ay
Submitted: 10 September 2018Reviewed: 30 November 2018Published: 08 January 2019
Open access peer-reviewed chapter
