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. 2022 Mar 21;11(6):1749.
doi: 10.3390/jcm11061749.

Over-Mutated Mitochondrial, Lysosomal and TFEB-Regulated Genes in Parkinson's Disease

Eulàlia Segur-Bailach  1 , Olatz Ugarteburu  1 , Frederic Tort  1 , Laura Texido  1 , Celia Painous  2 , Yaroslau Compta  2 , Maria José Martí  2 , Antonia Ribes  1 , Laura Gort  1
Affiliations

Over-Mutated Mitochondrial, Lysosomal and TFEB-Regulated Genes in Parkinson's Disease

Eulàlia Segur-Bailach et al. J Clin Med. .

Abstract

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.

Keywords: Parkinson’s disease; TFEB; WES; lysosomal; lysosomal diseases; mitochondrial; mitochondrial function; risk-factor.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Flowchart of the analytical strategy used in this study. * Except those variants classified in the HGMD as disease causing, dubious disease causing or iv/iv functional polymorphism.
Figure 2
Figure 2
Graphical representation by groups of the 1667 genes analysed in this study and the intersection among them.
Figure 3
Figure 3
Number of variants carried by PD patients and control individuals for each group of genes. PD, Parkinson’s disease patient cohort; C, control individuals cohort. * p < 0.05, ** p < 0.01.
See this image and copyright information in PMC

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