Abstract
Parkinson’s disease (PD) is a chronic neurodegenerative disease that has relatively slow progression with motor symptoms. Leucine-rich repeat kinase 2 (LRRK2) gene mutations and polymorphisms are suggested to be associated with PD. In this study, we aimed to investigate the association between single-nucleotide polymorphisms (SNPs) of the LRRK2 gene, namely, rs11176013, rs10878371, rs11835105, and PD. Genotypes of 132 PD cases and 133 healthy individuals were determined by qRT-PCR. Haplotype analysis was performed. Additionally, LRRK2 mRNA expression levels were determined in 83 PD cases and 55 healthy subjects. The relationship between LRRK2 mRNA levels, the target SNPs, and clinical data was also investigated. Our results indicated that the “GG” genotype and “G” allele of rs11176013 and the “CC” genotype and “C” allele of rs10878371 were more frequent in cases. The “GCG” haplotype was significantly more frequent in cases. LRRK2 mRNA expression levels in patients were significantly lower than those in healthy individuals. The patients with the “CC” genotype for rs10878371 and the “GG” genotype for rs11176013 had decreased LRRK2 mRNA levels. We found that the rs11176013 “GG” genotype and the rs10878371 “CC” genotype were less frequently seen in cases with akinetic rigid or combined akinetic rigid and tremor-dominant initial symptoms. Consequently, our results demonstrate that the rs11176013 and rs10878371 polymorphisms are associated with PD in a Turkish cohort, and moreover, these results suggest that these polymorphisms may affect the expression of the LRRK2 gene and disease progression and thus play a role in the pathogenesis of PD.
Similar content being viewed by others
Availability of Data and Materials
All data generated or analyzed during this study are included in this published article and its supplementary information files.
References
Aasly, J. O., Toft, M., Fernandez-Mata, I., Kachergus, J., Hulihan, M., White, L. R., et al. (2005). Clinical features of LRRK2-associated Parkinson’s disease in central Norway. Annals of Neurology, 57(5), 762–765. https://doi.org/10.1002/ana.20456.
Alaylioglu, M., Gezen-Ak, D., Dursun, E., Bilgic, B., Hanagasi, H., Ertan, T., et al. (2016). The association between clusterin and APOE polymorphisms and late-onset Alzheimer disease in a Turkish cohort. Journal of Geriatric Psychiatry and Neurology, 29(4), 221–226. https://doi.org/10.1177/0891988716640373.
Bardien, S., Marsberg, A., Keyser, R., Lombard, D., Lesage, S., Brice, A., et al. (2010). LRRK2 G2019S mutation: Frequency and haplotype data in South African Parkinson’s disease patients. Journal of Neural Transmission, 117(7), 847–853. https://doi.org/10.1007/s00702-010-0423-6.
Braak, H., & Del Tredici, K. (2008). A new look at the corticostriatal-thalamocortical circuit in sporadic Parkinson’s disease. Nervenarzt, 79(12), 1440–1445. https://doi.org/10.1007/s00115-008-2542-y.
Braak, H., Ghebremedhin, E., Rub, U., Bratzke, H., & Del Tredici, K. (2004). Stages in the development of Parkinson’s disease-related pathology. Cell and Tissue Research, 318(1), 121–134. https://doi.org/10.1007/s00441-004-0956-9.
Cardo, L. F., Coto, E., Ribacoba, R., Mata, I. F., Moris, G., Menendez, M., et al. (2014). The screening of the 3’UTR sequence of LRRK2 identified an association between the rs66737902 polymorphism and Parkinson’s disease. Journal of Human Genetics, 59(6), 346–348. https://doi.org/10.1038/jhg.2014.26.
Cook, D. A., Kannarkat, G. T., Cintron, A. F., Butkovich, L. M., Fraser, K. B., Chang, J., et al. (2017). LRRK2 levels in immune cells are increased in Parkinson’s disease. NPJ Parkinsons Disease, 3, 11. https://doi.org/10.1038/s41531-017-0010-8.
Devine, M. J., Kaganovich, A., Ryten, M., Mamais, A., Trabzuni, D., Manzoni, C., et al. (2011). Pathogenic LRRK2 mutations do not alter gene expression in cell model systems or human brain tissue. PLoS ONE, 6(7), e22489. https://doi.org/10.1371/journal.pone.0022489.
Dursun, E., Alaylioglu, M., Bilgic, B., Hanagasi, H., Lohmann, E., Atasoy, I. L., et al. (2016). Vitamin D deficiency might pose a greater risk for ApoEvarepsilon4 non-carrier Alzheimer’s disease patients. Neurological Sciences, 37(10), 1633–1643. https://doi.org/10.1007/s10072-016-2647-1.
Dursun, E., Gezen-Ak, D., & Yilmazer, S. (2011). A novel perspective for Alzheimer’s disease: Vitamin D receptor suppression by amyloid-beta and preventing the amyloid-beta induced alterations by vitamin D in cortical neurons. Journal of Alzheimer’s Disease, 23(2), 207–219. https://doi.org/10.3233/JAD-2010-101377.
Dzamko, N., Chua, G., Ranola, M., Rowe, D. B., & Halliday, G. M. (2013). Measurement of LRRK2 and Ser910/935 phosphorylated LRRK2 in peripheral blood mononuclear cells from idiopathic Parkinson’s disease patients. Journal of Alzheimer’s Disease, 3(2), 145–152. https://doi.org/10.3233/JPD-130174.
Funayama, M., Hasegawa, K., Kowa, H., Saito, M., Tsuji, S., & Obata, F. (2002). A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1. Annals of Neurology, 51(3), 296–301. https://doi.org/10.1002/ana.10113.
Galter, D., Westerlund, M., Carmine, A., Lindqvist, E., Sydow, O., & Olson, L. (2006). LRRK2 expression linked to dopamine-innervated areas. Annals of Neurology, 59(4), 714–719. https://doi.org/10.1002/ana.20808.
Gandhi, P. N., Chen, S. G., & Wilson-Delfosse, A. L. (2009). Leucine-rich repeat kinase 2 (LRRK2): A key player in the pathogenesis of Parkinson’s disease. Journal of Neuroscience Research, 87(6), 1283–1295. https://doi.org/10.1002/jnr.21949.
Gezen-Ak, D., Alaylioglu, M., Genc, G., Gunduz, A., Candas, E., Bilgic, B., et al. (2017). GC and VDR SNPs and vitamin D levels in Parkinson’s disease: The relevance to clinical features. NeuroMolecular Medicine, 19(1), 24–40. https://doi.org/10.1007/s12017-016-8415-9.
Gezen-Ak, D., Alaylioglu, M., Genc, G., Sengul, B., Keskin, E., Sordu, P., et al. (2020). Altered transcriptional profile of mitochondrial DNA-encoded OXPHOS subunits, mitochondria quality control genes, and ıntracellular ATP levels in blood samples of patients with Parkinson’s disease. Journal of Alzheimer’s Disease. https://doi.org/10.3233/JAD-191164.
Gezen-Ak, D., Atasoy, I. L., Candas, E., Alaylioglu, M., & Dursun, E. (2018). The transcriptional regulatory properties of amyloid beta 1-42 may ınclude regulation of genes related to neurodegeneration. NeuroMolecular Medicine, 20(3), 363–375. https://doi.org/10.1007/s12017-018-8498-6.
Gezen-Ak, D., Dursun, E., & Yilmazer, S. (2011). The effects of vitamin D receptor silencing on the expression of LVSCC-A1C and LVSCC-A1D and the release of NGF in cortical neurons. PLoS ONE, 6(3), e17553. https://doi.org/10.1371/journal.pone.0017553.
Goetz, C. G., Poewe, W., Rascol, O., Sampaio, C., Stebbins, G. T., Counsell, C., et al. (2004). Movement disorder society task force report on the Hoehn and Yahr staging scale: Status and recommendations. Movement Disorders, 19(9), 1020–1028. https://doi.org/10.1002/mds.20213.
Hoehn, M. M., & Yahr, M. D. (1967). Parkinsonism: Onset, progression and mortality. Neurology, 17(5), 427–442.
Huang, Y., Halliday, G. M., Vandebona, H., Mellick, G. D., Mastaglia, F., Stevens, J., et al. (2007). Prevalence and clinical features of common LRRK2 mutations in Australians with Parkinson’s disease. Movement Disorders, 22(7), 982–989. https://doi.org/10.1002/mds.21477.
Infante, J., Prieto, C., Sierra, M., Sanchez-Juan, P., Gonzalez-Aramburu, I., Sanchez-Quintana, C., et al. (2016). Comparative blood transcriptome analysis in idiopathic and LRRK2 G2019S-associated Parkinson’s disease. Neurobiology of Aging, 38(214), e211–e215. https://doi.org/10.1016/j.neurobiolaging.2015.10.026.
Ishihara, L., Gibson, R. A., Warren, L., Amouri, R., Lyons, K., Wielinski, C., et al. (2007). Screening for Lrrk2 G2019S and clinical comparison of Tunisian and North American Caucasian Parkinson’s disease families. Movement Disorders, 22(1), 55–61. https://doi.org/10.1002/mds.21180.
Jiang, E., Li, F., Jing, C., Li, P., Cui, H., Wang, B., et al. (2015). High-resolution melting analysis as a developed method for genotyping the PD susceptibility loci in LRRK2 gene. Journal of Clinical Laboratory Analysis, 29(4), 299–304. https://doi.org/10.1002/jcla.21769.
Kalia, L. V., Lang, A. E., Hazrati, L. N., Fujioka, S., Wszolek, Z. K., Dickson, D. W., et al. (2015). Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurology, 72(1), 100–105. https://doi.org/10.1001/jamaneurol.2014.2704.
Kalinderi, K., Bostantjopoulou, S., & Fidani, L. (2016). The genetic background of Parkinson’s disease: Current progress and future prospects. Acta Neurologica Scandinavica, 134(5), 314–326. https://doi.org/10.1111/ane.12563.
Khan, N. L., Jain, S., Lynch, J. M., Pavese, N., Abou-Sleiman, P., Holton, J. L., et al. (2005). Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson’s disease: Clinical, pathological, olfactory and functional imaging and genetic data. Brain, 128(Pt 12), 2786–2796. https://doi.org/10.1093/brain/awh667.
Kumari, U., & Tan, E. K. (2009). LRRK2 in Parkinson’s disease: Genetic and clinical studies from patients. FEBS Journal, 276(22), 6455–6463. https://doi.org/10.1111/j.1742-4658.2009.07344.x.
Lesage, S., & Brice, A. (2009). Parkinson’s disease: From monogenic forms to genetic susceptibility factors. Human Molecular Genetics, 18(R1), R48–R59. https://doi.org/10.1093/hmg/ddp012.
Lesage, S., Durr, A., & Brice, A. (2007). LRRK2: A link between familial and sporadic Parkinson’s disease? Pathologie Biologie, 55(2), 107–110. https://doi.org/10.1016/j.patbio.2006.06.001.
Li, J. Q., Tan, L., & Yu, J. T. (2014). The role of the LRRK2 gene in Parkinsonism. Molecular Neurodegeneration, 9, 47. https://doi.org/10.1186/1750-1326-9-47.
Li, H., Teo, Y. Y., & Tan, E. K. (2013). Patterns of linkage disequilibrium of LRRK2 across different races: Implications for genetic association studies. PLoS ONE, 8(9), e75041. https://doi.org/10.1371/journal.pone.0075041.
Lorenzo-Betancor, O., Samaranch, L., Ezquerra, M., Tolosa, E., Lorenzo, E., Irigoyen, J., et al. (2012). LRRK2 haplotype-sharing analysis in Parkinson’s disease reveals a novel p.S1761R mutation. Movement Disorders, 27(1), 146–151. https://doi.org/10.1002/mds.23968.
Lu, Y. W., & Tan, E. K. (2008). Molecular biology changes associated with LRRK2 mutations in Parkinson’s disease. Journal of Neuroscience Research, 86(9), 1895–1901. https://doi.org/10.1002/jnr.21656.
Mata, I. F., Checkoway, H., Hutter, C. M., Samii, A., Roberts, J. W., Kim, H. M., et al. (2012). Common variation in the LRRK2 gene is a risk factor for Parkinson’s disease. Movement Disorders, 27(14), 1822–1825. https://doi.org/10.1002/mds.25226.
Mata, I. F., Checkoway, H., Hutter, C. M., Samii, A., Roberts, J. W., Kim, H. M., et al. (2013). Common variation in the LRRK2 gene is a risk factor for Parkinson’s disease. Movement Disorders, 27(14), 1822–1825. https://doi.org/10.1002/mds.25226.
Miklossy, J., Arai, T., Guo, J. P., Klegeris, A., Yu, S., McGeer, E. G., et al. (2006). LRRK2 expression in normal and pathologic human brain and in human cell lines. Journal of Neuropathology and Experimental Neurology, 65(10), 953–963. https://doi.org/10.1097/01.jnen.0000235121.98052.54.
Paisan-Ruiz, C., Jain, S., Evans, E. W., Gilks, W. P., Simon, J., van der Brug, M., et al. (2004). Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron, 44(4), 595–600. https://doi.org/10.1016/j.neuron.2004.10.023.
Paisan-Ruiz, C., Nath, P., Washecka, N., Gibbs, J. R., & Singleton, A. B. (2008). Comprehensive analysis of LRRK2 in publicly available Parkinson’s disease cases and neurologically normal controls. Human Mutation, 29(4), 485–490. https://doi.org/10.1002/humu.20668.
Pan, R., & Xiao, P. (2016). Quantitative haplotyping of PCR products by nonsynchronous pyrosequencing with di-base addition. Analytical and Bioanalytical Chemistry, 408(29), 8263–8271. https://doi.org/10.1007/s00216-016-9936-7.
Patra, B., Parsian, A. J., Racette, B. A., Zhao, J. H., Perlmutter, J. S., & Parsian, A. (2009). LRRK2 gene G2019S mutation and SNPs [haplotypes] in subtypes of Parkinson’s disease. Parkinsonism & Related Disorders, 15(3), 175–180. https://doi.org/10.1016/j.parkreldis.2008.05.004.
Ross, O. A., Soto-Ortolaza, A. I., Heckman, M. G., Aasly, J. O., Abahuni, N., Annesi, G., et al. (2011). Association of LRRK2 exonic variants with susceptibility to Parkinson’s disease: A case-control study. The Lancet Neurology, 10(10), 898–908. https://doi.org/10.1016/S1474-4422(11)70175-2.
Ross, O. A., Wilhoite, G. J., Bacon, J. A., Soto-Ortolaza, A., Kachergus, J., Cobb, S. A., et al. (2010). LRRK2 variation and Parkinson’s disease in African Americans. Movement Disorders, 25(12), 1973–1976. https://doi.org/10.1002/mds.23163.
Schapira, A. H. (2006). The importance of LRRK2 mutations in Parkinson disease. Archives of Neurology, 63(9), 1225–1228. https://doi.org/10.1001/archneur.63.9.1225.
Schulze, M., Sommer, A., Plotz, S., Farrell, M., Winner, B., Grosch, J., et al. (2018). Sporadic Parkinson’s disease derived neuronal cells show disease-specific mRNA and small RNA signatures with abundant deregulation of piRNAs. Acta Neuropathologica Communications, 6(1), 58. https://doi.org/10.1186/s40478-018-0561-x.
Sharma, S., Bandopadhyay, R., Lashley, T., Renton, A. E., Kingsbury, A. E., Kumaran, R., et al. (2011). LRRK2 expression in idiopathic and G2019S positive Parkinson’s disease subjects: A morphological and quantitative study. Neuropathology and Applied Neurobiology, 37(7), 777–790. https://doi.org/10.1111/j.1365-2990.2011.01187.x.
Simunovic, F., Yi, M., Wang, Y., Macey, L., Brown, L. T., Krichevsky, A. M., et al. (2009). Gene expression profiling of substantia nigra dopamine neurons: Further insights into Parkinson’s disease pathology. Brain, 132(Pt 7), 1795–1809. https://doi.org/10.1093/brain/awn323.
Singleton, A. B., Farrer, M. J., & Bonifati, V. (2013). The genetics of Parkinson’s disease: Progress and therapeutic implications. Movement Disorders, 28(1), 14–23. https://doi.org/10.1002/mds.25249.
Soto-Ortolaza, A. I., Heckman, M. G., Labbe, C., Serie, D. J., Puschmann, A., Rayaprolu, S., et al. (2013). GWAS risk factors in Parkinson’s disease: LRRK2 coding variation and genetic interaction with PARK16. American Journal of Neurodegenerative Disease, 2(4), 287–299.
Spatola, M., & Wider, C. (2014). Genetics of Parkinson’s disease: The yield. Parkinsonism & Related Disorders, 20(Suppl 1), S35–S38. https://doi.org/10.1016/S1353-8020(13)70011-7.
Thevenet, J., Pescini Gobert, R., Hooft van Huijsduijnen, R., Wiessner, C., & Sagot, Y. J. (2011). Regulation of LRRK2 expression points to a functional role in human monocyte maturation. PLoS ONE, 6(6), e21519. https://doi.org/10.1371/journal.pone.0021519.
Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., et al. (2004). Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron, 44(4), 601–607. https://doi.org/10.1016/j.neuron.2004.11.005.
Acknowledgements
The present work was supported by the Research Fund of Istanbul University-Cerrahpasa. Project Nos. 58745, 27781, 26989. The English of the manuscript has been edited by American Journal Experts (AJE) Language Editing Service with the Reference Number 36C1-0FDB-3704-D03B-B8D5.
Author information
Authors and Affiliations
Contributions
Conceptualization: DGA, SE, ED; Data Curation: EC, DGA, MA, BŞ, GG, AG, HA, GK, SE, ED; Formal Analysis: DGA, EC, ED; Funding Acquisition: SY; Investigation: SY, EC, DGA, ED; Methodology: DGA, EC, MA, GG, BŞ, SY, SE, ED; Project Administration: SY, DGA, ED; Resources; SY, DGA, ED; Supervision: SY, SE, DGA, ED; Validation: DGA, ED; Writing—Original Draft Preparation: DGA, ED; Writing—Review & Editing: DGA, SY, SE, ED. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical Approval
Participants in the present study were treated according to the ethical principles for medical research involving human participants described in the World Medical Association’s Declaration of Helsinki, and the study was approved by the Ethics Committee of Istanbul University.
Informed Consent
Signed informed consent was obtained from all study participants.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Yılmazer, S., Candaş, E., Genç, G. et al. Low Levels of LRRK2 Gene Expression are Associated with LRRK2 SNPs and Contribute to Parkinson’s Disease Progression. Neuromol Med 23, 292–304 (2021). https://doi.org/10.1007/s12017-020-08619-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-020-08619-x