Abstract
Introduction. Post-transcriptional and post-translational modifications of the alpha-synuclein protein are considered important links in the pathogenesis of Parkinson’s disease (PD) and multiple system atrophy (MSA). Regulation of mRNA stability and translational activity is primarily provided by the 3’untranslated region (3’UTR). The proportion of long 3’UTRs (3’UTR-L) is currently considered as a risk factor for PD.
Aim of the study. To assess the proportion of 3’UTR-L SNCA transcripts with in patients with PD and MSA, and the influence of single nucleotide polymorphisms (SNPs) in this gene on the 3’UTR-L/total SNCA mRNA ratio.
Material and methods. The concentration of SNCA and 3’UTR-L mRNAs was determined in blood leukocytes of 84 patients (Russian population) with PD, 50 patients with MSA, and 49 healthy volunteers, by quantitative RT-PCR. The proportion of 3’UTR-L was expressed as a percentage of the total SNCA mRNA. SNP was determined by Sanger sequencing.
Results. Overall, the proportion of 3’UTR-L did not differ significantly between the PD, MSA, and control groups: in PD, the median proportion of 3’UTR-L was 30.9%, in MSA – 28.5%, in the control group – 29.8%, p = 0.21. A decrease in the proportion of 3’UTR-L by 15–21% relative to the median value for the group was detected in PD patients in association with the «risk» genotype GG at rs356168, rs356165, and rs3756063; in the MSA patient group, a decrease of 13–15% was also noted in relationship with the GG genotype at rs356168, rs356165, and the CC genotype at rs2737029. An increase in the proportion of 3’UTR-L by 17% was noted only in the PD group for “protective” genotype AA at rs356168 and rs356165.
Keywords
Authors and affiliations
https://elibrary.ru/belloh L.S. Karan(1), N.Yu. Abramycheva(1), I.V. Minaev(1), T.A. Krutyakova(2), A.O. Protopopova(1),
A.R. Protsenko(1), I.A. Berdalina(1),E.Yu. Fedotova(1), S.N. Illarioshkin(1),
1Russian Center of Neurology and Neuroscience, Volokolamskoye shosse, 80, Moscow, 125367, Russian Federation;
2Lomonosov Moscow State University, Leninskie Gory, 1, Moscow, 119991, Russian Federation
References
Junn E., Lee K.W., Jeong B.S., Chan T.W., Im J.Y., Mouradian M.M. Repression of alpha-synuclein expression and toxicity by microRNA-7. Proc Natl Acad Sci USA. 2009; 106 (31): 13052–7. DOI: 10.1073/pnas.0906277106.
2. Doxakis E. Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153. J. Biol. Chem. 2010; 285 (17): 12726–34. DOI: 10.1074/jbc.M109.086827.
3. Uwatoko H., Hama Y., Iwata I.T., Shirai S., Matsushima M., Yabe I., Utsumi J., Sasaki H. Identification of plasma microRNA expression changes in multiple system atrophy and Parkinson’s disease. Mol. Brain. 2019; 12 (1): 49. DOI: 10.1186/s13041-019-0471-2.
4. Soldner F., Stelzer Y., Shivalila C.S., Abraham B.J., Latourelle J.C., Barrasa M.I., Goldmann J., Myers R.H., Young R.A., Jaenisch R. Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature. 2016; 533 (7601): 95–9. DOI: 10.1038/nature17939.
5. Marchese D., Botta-Orfila T., Cirillo D., Rodriguez J.A., Livi C.M., Fernández-Santiago R., Ezquerra M., Marti M.J., Bechara E., Tartaglia G.G. Catalan M.S.A. Registry (CMSAR). Discovering the 3’ UTR-mediated regulation of alpha-synuclein. Nucleic Acids Res. 2017; 45 (22): 12888–903. DOI: 10.1093/nar/gkx1048.
6. Rhinn H., Qiang L., Yamashita T., Rhee D., Zolin A., Vanti W., Abeliovich A. Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson’s disease pathology. Nat Commun. 2012; 3: 1084. DOI: 10.1038/ncomms2032.
7. Sotiriou S., Gibney G., Baxevanis A.D., Nussbaum R.L. A single nucleotide polymorphism in the 3’UTR of the SNCA gene encoding alpha-synuclein is a new potential susceptibility locus for Parkinson disease. Neurosci Lett. 2009; 461 (2): 196–201. DOI: 10.1016/j.neulet.2009.06.034.
8. Bae B., Miura P. Emerging Roles for 3’ UTRs in Neurons. Int. J. Mol. Sci. 2020; 21 (10): 3413. DOI: 10.3390/ijms21103413
9. Blažeković A., Jerčić K.G., Borovečki F. SNCA 3’ UTR Genetic Variants in Patients with Parkinson’s Disease. Biomolecules. 2021; 11 (12): 1799. DOI: 10.3390/biom11121799.
10. Satake W., Nakabayashi Y., Mizuta I. et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nature genetics. 2009; 41: 1303–7. DOI: 10.1038/ng.485
11. Simon-Sanchez J., Schulte C., Bras J.M. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nature genetics. 2009; 41: 1308–12. DOI: 10.1038/ng.487
12. Nalls N.A., Plagnol V., Hernandez D.G. International Parkinson Disease Genomics Consortium. Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet. 2011; 377 (9766): 641–9. DOI: 10.1016/S0140-6736(10)62345-8
13. Szwedo A.A., Pedersen C.C., Anastasia Ushakova A et al. Association of SNCA Parkinson’s Disease Risk Polymorphisms With Disease Progression in Newly Diagnosed Patients. Frontiers in Neurology. 2021; 11: 620585. DOI: 10.3389/fneur.2020.620585
14. Zhang Y., Shu L., Qiying Sun O. et al. A Comprehensive Analysis of the Association Between SNCA Polymorphisms and the Risk of Parkinson’s Disease. Front Mol. Neurosci. 2018; 11: 391. DOI: 10.3389/fnmol.2018.00391
15. Абрамычева Н.Ю., Карань Л.С., Протопопова А.О., Минаев И.В., Бердалина И.А., Федотова Е.Ю., Иллариошкин С.Н. Полиморфные варианты гена SNCA и риск развития синуклеинопатий. Анналы клинической и экспериментальной неврологии. 2025; 19 (1): 43–52. DOI: 10.17816/ACEN.1220. [Abramycheva N., Karan L., Protopopova A., Minaev I., Berdalina I., Fedotova E., Illarioshkin S. Polymorphisms in the SNCA gene and the risk of synucleopathy. Annals of Clinical and Experimental Neurology. 2025; 19 (1): 43–52. DOI: 10.17816/ACEN.1220
16. Soldner F., Stelzer Y., Shivalila C.S., Abraham B.J., Latourelle J.C., Barrasa M.I., Goldmann J., Myers R.H., Young R.A., Jaenisch R. Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature. 2016; 533 (7601): 95–9. DOI: 10.1038/nature17939.
17. Locascio J.J., Eberly S., Liao Z., Liu G., Hoesing A.N., Duong K., Trisini-Lipsanopoulos A., Dhima K., Hung A.Y., Flaherty A.W., Schwarzschild M.A., Hayes M.T., Wills A.M., Shivraj Sohur U., Mejia N.I., Selkoe D.J., Oakes D., Shoulson I., Dong X., Marek K., Zheng B., Ivinson A., Hyman B.T., Growdon J.H., Sudarsky L.R., Schlossmacher M.G., Ravina B., Scherzer C.R. Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson’s disease. Brain. 2015; 138 (9): 2659–71. DOI: 10.1093/brain/awv202.
18. Pihlstrøm L., Berge V., Rengmark A., Toft M. Parkinson’s disease correlates with promoter methylation in the α-synuclein gene. Mov Disord. 2015; 30 (4): 577–80. DOI: 10.1002/mds.26073.
19. Wei Y., Yang N., Xu Q., Sun Q., Guo J., Li K., Liu Z., Yan X., Zhu X., Tang B. The rs3756063 polymorphism is associated with SNCA methylation in the Chinese Han population. J. Neurol Sci. 2016; 367: 11–4. DOI: 10.1016/j.jns.2016.05.037.