Segur-Bailach Eulàlia, Ugarteburu Olatz, Tort Frederic, Texido Laura, Painous Celia, Compta Yaroslau, Martí Maria José, Ribes Antonia, Gort Laura
Secció d'Errors Congènits del Metabolisme-IBC, Servei de Bioquímica i Genètica Molecular, CDB, Hospital Clínic de Barcelona, IDIBAPS, CIBERER, 08028 Barcelona, Spain.
Parkinson's Disease & Movement Disorders Unit, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED, European Reference Network for Rare Neurological Diseases (ERN-RND), Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain.
J Clin Med. 2022 Mar 21;11(6):1749. doi: 10.3390/jcm11061749.
The association between Parkinson's disease (PD) and mutations in genes involved in lysosomal and mitochondrial function has been previously reported. However, little is known about the involvement of other genes or cellular mechanisms. We aim to identify novel genetic associations to better understand the pathogenesis of PD. We performed WES in a cohort of 32 PD patients and 30 age-matched controls. We searched for rare variants in 1667 genes: PD-associated, related to lysosomal function and mitochondrial function and TFEB-regulated. When comparing the PD patient cohort with that of age matched controls, a statistically significant burden of rare variants in the previous group of genes were identified. In addition, the Z-score calculation, using the European population database (GnomAD), showed an over-representation of particular variants in 36 genes. Interestingly, 11 of these genes are implicated in mitochondrial function and 18 are TFEB-regulated genes. Our results suggest, for the first time, an involvement of TFEB-regulated genes in the genetic susceptibility to PD. This is remarkable as TFEB factor has been reported to be sequestered inside Lewy bodies, pointing to a role of TFEB in the pathogenesis of PD. Our data also reinforce the involvement of lysosomal and mitochondrial mechanisms in PD.
帕金森病（PD）与参与溶酶体和线粒体功能的基因突变之间的关联此前已有报道。然而，对于其他基因或细胞机制的参与情况知之甚少。我们旨在识别新的基因关联，以更好地理解PD的发病机制。我们对32例PD患者和30例年龄匹配的对照进行了全外显子组测序（WES）。我们在1667个基因中搜索罕见变异：与PD相关、与溶酶体功能和线粒体功能相关以及受转录因子EB（TFEB）调控的基因。在将PD患者队列与年龄匹配的对照队列进行比较时，在前一组基因中发现了具有统计学意义的罕见变异负担。此外，使用欧洲人群数据库（GnomAD）进行的Z评分计算显示，36个基因中特定变异的出现频率过高。有趣的是，这些基因中有11个与线粒体功能有关，18个是受TFEB调控的基因。我们的结果首次表明，受TFEB调控的基因参与了PD的遗传易感性。这很显著，因为据报道TFEB因子被隔离在路易小体内，这表明TFEB在PD发病机制中发挥作用。我们的数据也进一步证实了溶酶体和线粒体机制在PD中的参与。
