Petkova-Kirova Polina, Baas Stephan, Wagenpfeil Gudrun, Hartz Philip, Unger Marcus Michael, Bernhardt Rita
Institut für Biochemie, Fachbereich Biologie, Naturwissenschaftlich-Technische Fakultät, Universität des Saarlandes, Saarbrücken, Germany.
SHG Kliniken, Saarbrücken, Germany.
Front Pharmacol. 2023 Aug 4;14:1244516. doi: 10.3389/fphar.2023.1244516. eCollection 2023.
Parkinson's disease (PD) is one of the most frequent neurological diseases affecting millions of people worldwide. While the majority of PD cases are of unknown origin (idiopathic), about 5%-10% are familial and linked to mutations in different known genes. However, there are also people with a genetic predisposition to PD who do not develop the disease. To elucidate factors leading to the manifestation of PD we compared the occurrence of single nucleotide polymorphisms (SNPs) in various cytochrome P450 (P450) genes in people with a genetic predisposition and suffering from PD (GPD) to that of people, who are genetically predisposed, but show no symptoms of the disease (GUN). We used the PPMI (Parkinson's Progression Markers Initiative) database and the gene sequences of all 57 P450s as well as their three redox partners. Corresponding odds ratios (OR) and confidence intervals (CI) were calculated to assess the incidence of the various SNPs in the two groups of individuals and consequently their relation to PD. We identified for the first time SNPs that are significantly (up to 10fold!) over- or under-represented in GPD patients compared to GUN. SNPs with OR > 5 were found in 10 P450s being involved in eicosanoid, vitamin A and D metabolism as well as cholesterol degradation pointing to an important role of endogenous factors for the manifestation of PD clinical symptoms. Moreover, 12 P450s belonging to all P450 substrate classes as well as POR have SNPs that are significantly under-represented (OR < 0.2) in GPD compared to GUN, indicating a protective role of those SNPs and the corresponding P450s regarding disease advancement. To the best of our knowledge our data for the first time demonstrate an association between known PD predisposition genes and SNPs in other genes, shown here for different P450 genes and for their redox partner POR, which promote the manifestation of the disease in familial PD. Our results thus shed light onto the pathogenesis of PD, especially the switch from GUN to GPD and might further help to advance novel strategies for preventing the development or progression of the disease.
帕金森病（PD）是全球影响数百万人的最常见神经系统疾病之一。虽然大多数帕金森病病例病因不明（特发性），但约5%-10%为家族性，与不同已知基因的突变有关。然而，也有一些具有帕金森病遗传易感性的人并未发病。为了阐明导致帕金森病表现的因素，我们比较了具有帕金森病遗传易感性且患有帕金森病（GPD）的人群与具有遗传易感性但未出现该病症状（GUN）的人群中各种细胞色素P450（P450）基因的单核苷酸多态性（SNP）的发生情况。我们使用了帕金森病进展标志物倡议（PPMI）数据库以及所有57种P450及其三种氧化还原伴侣的基因序列。计算相应的优势比（OR）和置信区间（CI），以评估两组个体中各种SNP的发生率，进而评估它们与帕金森病的关系。我们首次发现，与GUN相比，GPD患者中某些SNP的出现显著（高达10倍！）过多或过少。在参与类花生酸、维生素A和D代谢以及胆固醇降解的10种P450中发现OR>5的SNP，这表明内源性因素在帕金森病临床症状的表现中起重要作用。此外，与GUN相比，属于所有P450底物类别的12种P450以及POR的SNP在GPD中显著过少（OR<0.2），表明这些SNP和相应的P450对疾病进展具有保护作用。据我们所知，我们的数据首次证明了已知的帕金森病易感基因与其他基因中的SNP之间的关联，这里以不同的P450基因及其氧化还原伴侣POR为例，这些基因在家族性帕金森病中促进了疾病的表现。因此，我们的结果揭示了帕金森病的发病机制，特别是从GUN到GPD的转变，可能进一步有助于推进预防该疾病发展或进展的新策略。
