MTOR Pathway-Based Discovery of Genetic Susceptibility to L-DOPA-Induced Dyskinesia in Parkinson’s Disease Patients
Dyskinesia induced by L-DOPA administration (LID) is one of the most invalidating adverse effects of the gold standard treatment restoring dopamine transmission in Parkinson’s disease (PD). However, LID manifestation in parkinsonian patients is variable and heterogeneous. Here, we performed a candidate genetic pathway analysis of the mTOR signaling cascade to elucidate a potential genetic contribution to LID susceptibility, since mTOR inhibition ameliorates LID in PD animal models. We screened 64 single nucleotide polymorphisms (SNPs) mapping to 57 genes of the mTOR pathway in a retrospective cohort of 401 PD cases treated with L-DOPA (70 PD with moderate/severe LID and 331 with no/mild LID). We performed classic allelic, genotypic, and epistatic analyses to evaluate the association of individual or combinations of SNPs with LID onset and with LID severity after initiation of L-DOPA treatment. As for the time to LID onset, we found significant associations with SNP rs1043098 in the EIF4EBP2 gene and also with an epistatic interaction involving EIF4EBP2 rs1043098, RICTOR rs2043112, and PRKCA rs4790904. For LID severity, we found significant association with HRAS rs12628 and PRKN rs1801582 and also with a four-loci epistatic combination involving RPS6KB1 rs1292034, HRAS rs12628, RPS6KA2 rs6456121, and FCHSD1 rs456998. These findings indicate that the mTOR pathway contributes genetically to LID susceptibility. Our study could help to identify the most susceptible PD patients to L-DOPA in order to prevent the appearance of early and/or severe LID in a future. This information could also be used to stratify PD patients in clinical trials in a more accurate way.
KeywordsmTOR L-DOPA Dyskinesia Single nucleotide polymorphism Parkinson’s disease Epistasia
Minor allele frequency
Multifactorial dimensionality reduction
Mechanistic target of rapamycin complex
Single nucleotide polymorphisms
Time to dyskinesia
Time to L-DOPA
Time to LID Peak
L-DOPA equivalent dose
We thank Dr. Jason H. Moore and Dr. Peter Andrews for their kind assessment with the MDR software use and helpful discussion. We also thank Dr. Roger Anglada from the Genomics Core Facility from the Universitat Pompeu Fabra (Barcelona) for his work and helpful assessment with sample analysis. We acknowledge the CERCA Program from the Generalitat de Catalunya and the FEDER Program from the European Union to IDIBAPS.
Compliance of Ethical Standards
All subjects were recruited at the Movement Disorders Unit from the Hospital Clínic Provincial de Barcelona. Written informed consent and whole blood samples were obtained from each subject. The study was approved by the Ethics Committee of the Hospital Clínic de Barcelona.
Conflict of Interest
This work has been granted by the Michael J. Fox Foundation, Dyskinesia Challenge 2014. The technology derived from this work has been filed for a European patent application (File number: EP17382248), to develop a diagnostics method of personalized medicine for PD patients.
- 2.Fahn S (2008) Clinical aspects of Parkinson disease. In: Parkinson’s disease, 1st edn. Academic Press, New York, p 1–8Google Scholar
- 8.Malagelada C, Ryu EJ, Biswas SC, Jackson-Lewis V, Greene LA (2006) RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson’s disease by a mechanism involving mammalian target of rapamycin inactivation. J Neurosci 26:9996–10005. https://doi.org/10.1523/JNEUROSCI.3292-06.2006 CrossRefPubMedGoogle Scholar
- 21.Fahn S, Elton R (1987) Unified Parkinson’s disease rating scale. In: Recent developments in Parkinson’s disease, 2nd edn. Macmillan Healthcare Information, Florham Park, p 153–163Google Scholar
- 22.Fernández-Santiago R, Iranzo A, Gaig C, Serradell M, Fernández M, Tolosa E, Santamaría J, Ezquerra M (2016) Absence of LRRK2 mutations in a cohort of patients with idiopathic REM sleep behavior disorder. Neurology 86:1072–1073. https://doi.org/10.1212/WNL.0000000000002304 CrossRefPubMedGoogle Scholar
- 26.Reijmerink NE, Bottema RWB, Kerkhof M, Gerritsen J, Stelma FF, Thijs C, van Schayck CP, Smit HA et al (2010) TLR-related pathway analysis: novel gene-gene interactions in the development of asthma and atopy. Allergy 65:199–207. https://doi.org/10.1111/j.1398-9995.2009.02111.x CrossRefPubMedGoogle Scholar
- 28.Holmans P, Moskvina V, Jones L, Sharma M, The International Parkinson's Disease Genomics Consortium (IPDGC), Vedernikov A, Buchel F, Sadd M et al (2013) A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson’s disease. Hum Mol Genet 22:1039–1049. https://doi.org/10.1093/hmg/dds492 CrossRefPubMedGoogle Scholar
- 29.Mas S, Gassó P, Ritter MA, Malagelada C, Bernardo M, Lafuente A (2015) Pharmacogenetic predictor of extrapyramidal symptoms induced by antipsychotics: Multilocus interaction in the mTOR pathway. Eur Neuropsychopharmacol 25:51–59. https://doi.org/10.1016/j.euroneuro.2014.11.011 CrossRefPubMedGoogle Scholar
- 32.Cheshire P, Bertram K, Ling H, O'Sullivan SS, Halliday G, McLean C, Bras J, Foltynie T et al (2014) Influence of single nucleotide polymorphisms in COMT, MAO-A and BDNF genes on dyskinesias and levodopa use in Parkinson’s disease. Neurodegener Dis 13:24–28. https://doi.org/10.1159/000351097 PubMedCrossRefGoogle Scholar
- 33.Devos D, Lejeune S, Cormier-Dequaire F, Tahiri K, Charbonnier-Beaupel F, Rouaix N, Duhamel A, Sablonnière B et al (2014) Dopa-decarboxylase gene polymorphisms affect the motor response to l-dopa in Parkinson’s disease. Parkinsonism Relat Disord 20:170–175. https://doi.org/10.1016/j.parkreldis.2013.10.017 CrossRefPubMedGoogle Scholar
- 34.Kaplan N, Vituri A, Korczyn AD, Cohen OS, Inzelberg R, Yahalom G, Kozlova E, Milgrom R et al (2014) Sequence variants in SLC6A3, DRD2, and BDNF genes and time to levodopa-induced dyskinesias in Parkinson’s disease. J Mol Neurosci 53:183–188. https://doi.org/10.1007/s12031-014-0276-9 CrossRefPubMedGoogle Scholar
- 37.Grünblatt E, Mandel S, Jacob-Hirsch J et al (2004) Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes. J Neural Transm 111:1543–1573. https://doi.org/10.1007/s00702-004-0212-1 CrossRefPubMedGoogle Scholar
- 39.Zhang Y, Meredith GE, Mendoza-Elias N, Rademacher DJ, Tseng KY, Steece-Collier K (2013) Aberrant restoration of spines and their synapses in L-DOPA-induced dyskinesia: involvement of corticostriatal but not thalamostriatal synapses. J Neurosci 33:11655–11667. https://doi.org/10.1523/JNEUROSCI.0288-13.2013 CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Mandel SA, Youdim MBH, Riederer P, et al (2013) Peripheral blood gene markers for early diagnosis of Parkinson’s disease. (Patent reference number: US20130217028A1) Google Patents web. https://patents.google.com/patent/US20130217028. Accessed 26 October 2010
- 41.Charbonnier-Beaupel F, Malerbi M, Alcacer C, Tahiri K, Carpentier W, Wang C, During M, Xu D et al (2015) Gene expression analyses identify Narp contribution in the development of L-DOPA-induced dyskinesia. J Neurosci 35:96–111. https://doi.org/10.1523/JNEUROSCI.5231-13.2015 CrossRefPubMedGoogle Scholar
- 55.Huang RS, Duan S, Shukla SJ, Kistner EO, Clark TA, Chen TX, Schweitzer AC, Blume JE et al (2007) Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach. Am J Hum Genet 81:427–437. https://doi.org/10.1086/519850 CrossRefPubMedPubMedCentralGoogle Scholar