Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India.
Livestock Farming, & Bioresources Technology, Tamil Nadu, India.
J Mol Neurosci. 2022 Aug;72(8):1724-1737. doi: 10.1007/s12031-022-02028-4. Epub 2022 Jun 8.
Parkinson's disease (PD) is an ageing disorder caused by dopaminergic neuron depletion with age. Growing research in the field of metabolomics is expected to play a major role in PD diagnosis, prognosis and therapeutic development. In this study, we looked at how SNCA and GBA1 gene mutations, as well as metabolomic abnormalities of kynurenine and cholesterol metabolites, were linked to alpha-synuclein (α-syn) and clinical characteristics in three different PD age groups. In all three age groups, a metabolomics analysis revealed an increased amount of 27-hydroxycholesterol (27-OHC) and a lower level of kynurenic acid (KYNA). The effect of 27-OHC on SNCA and GBA1 modifications was shown to be significant (P < 0.05) only in the A53T variant of the SNCA gene in late-onset and early-onset PD groups, whereas GBA1 variants were not. Based on the findings, we observed that the increase in 27-OHC would have elevated α-syn expression, which triggered the changes in the SNCA gene but not in the GBA1 gene. Missense variations in the SNCA and GBA1 genes were investigated using the sequencing technique. SNCA mutation A53T has been linked to increased PD symptoms, but there is no phenotypic link between GBA1 and PD. As a result of the data, we hypothesise that cholesterol and kynurenine metabolites play an important role in PD, with the metabolite 27-OHC potentially serving as a PD biomarker. These findings will aid in the investigation of pathogenic causes as well as the development of therapeutic and preventative measures for PD.
帕金森病（PD）是一种衰老性疾病，由多巴胺能神经元随年龄增长而耗竭引起。代谢组学领域的研究不断深入，有望在 PD 的诊断、预后和治疗开发中发挥重要作用。在这项研究中，我们研究了 SNCA 和 GBA1 基因突变以及色氨酸和胆固醇代谢物的代谢组学异常与α-突触核蛋白（α-syn）和三个不同 PD 年龄组的临床特征之间的关系。在所有三个年龄组中，代谢组学分析显示 27-羟胆固醇（27-OHC）的含量增加，而犬尿氨酸酸（KYNA）的水平降低。结果表明，只有在晚发型和早发型 PD 组的 SNCA 基因 A53T 变异中，27-OHC 对 SNCA 和 GBA1 修饰的影响才具有统计学意义（P<0.05），而 GBA1 变体则没有。根据这些发现，我们观察到 27-OHC 的增加会导致α-syn 表达升高，从而触发 SNCA 基因的变化，但不会触发 GBA1 基因的变化。使用测序技术研究了 SNCA 和 GBA1 基因的错义变异。SNCA 基因的 A53T 突变与 PD 症状的增加有关，但 GBA1 与 PD 之间没有表型联系。基于这些数据，我们假设胆固醇和犬尿氨酸代谢物在 PD 中起重要作用，代谢物 27-OHC 可能作为 PD 的生物标志物。这些发现将有助于研究发病原因以及开发 PD 的治疗和预防措施。
