Department of Biomedicine, Unit of Biochemistry, Faculty of Medicine, Universitat de Barcelona, 08036, Barcelona, Catalonia, Spain.
Institut de Neurociències, Universitat de Barcelona, 08036, Barcelona, Catalonia, Spain.
Mol Neurobiol. 2019 Mar;56(3):2092-2100. doi: 10.1007/s12035-018-1219-1. Epub 2018 Jul 10.
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.
左旋多巴（L-DOPA）治疗引起的运动障碍（LID）是帕金森病（PD）恢复多巴胺传递的金标准治疗中最具破坏性的不良反应之一。然而，帕金森病患者的 LID 表现是可变的和异质的。在这里，我们对 mTOR 信号级联的候选基因途径进行了分析，以阐明其对 LID 易感性的潜在遗传贡献，因为 mTOR 抑制可改善 PD 动物模型中的 LID。我们在接受 L-DOPA 治疗的 401 例 PD 病例的回顾性队列中筛选了 64 个单核苷酸多态性（SNP），这些 SNP 映射到 mTOR 途径的 57 个基因（70 例 PD 患者有中/重度 LID，331 例患者无/轻度 LID）。我们进行了经典的等位基因、基因型和上位性分析，以评估单个 SNP 或 SNP 组合与 LID 发病和 L-DOPA 治疗开始后 LID 严重程度的关联。对于 LID 发病时间，我们发现 EIF4EBP2 基因中的 SNP rs1043098 和涉及 EIF4EBP2 rs1043098、RICTOR rs2043112 和 PRKCA rs4790904 的上位性相互作用与 SNP rs1043098 显著相关。对于 LID 严重程度，我们发现 HRAS rs12628 和 PRKN rs1801582 与涉及 RPS6KB1 rs1292034、HRAS rs12628、RPS6KA2 rs6456121 和 FCHSD1 rs456998 的四个基因座的上位性组合显著相关。这些发现表明 mTOR 途径在遗传上有助于 LID 易感性。我们的研究可以帮助确定对 L-DOPA 最敏感的 PD 患者，以便在未来预防早期和/或严重的 LID。这些信息还可以更准确地将 PD 患者分层用于临床试验。
