The impact of Parkinson’s on the basis of sex depends on genes – Health and Medicine

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Deciphering the mechanisms, essential to establish diagnoses and individual therapies by gender.

Between 120,000 and 150,000 people suffer from Parkinson’s disease (PD) in Spain and each year some 10,000 new cases are diagnosed, according to the latest data from the Spanish Society of Neurology (SEN). Added to this is the longevity of the population, which points to a significant increase in incidence in the coming years.

Thus, the advances and novelties in the knowledge of the pathology acquire special relevance, such as that carried out by the Bioinformatics and Biostatistics Unit (UBB) of the Príncipe Felipe de Valencia Research Center (CIPF), led by Francisco García-García.

Specifically, as shown by a study published in Biology of Sex Differences, by Springer Nature, García-García and his team have been able to identify a set of molecular mechanisms that can explain the differences by sex in PD: different profiles in inflammation, mitochondrial dysfunction and oxidative stress.

In addition, this study, which is part of the DifNerOmics project: Study of sex differences in neurodegenerative diseases with integrative approaches to omic data and biomedical imaging, has revealed that 237 genes show significantly differential expression between men and women, in the substantia nigra , the area of ​​the brain most affected in this disease and where the neurons that transmit and conduct dopamine are found.

Regarding the genesis of the project, explains García-García, “PD presents clinical and epidemiological differences between men and women. However, there is no complete understanding of the molecular mechanisms that explain these differences.”

For this reason, identifying and understanding these mechanisms “is a necessity that can provide key information to improve diagnoses and treatments personalized by sex,” the author points out.

The scientific collaboration between teams from the Valencian Institute of Oncology (IVO), the Fisabio Mixed Biomedical Imaging Unit and the CIPF “has provided the appropriate framework for the development of this multidisciplinary research”.

Systematic review and bioinformatics

The computational strategy, points out the researcher, included two phases: a systematic review of all published studies on PD, whose gene expression data were available in public repositories; and the bioinformatic analysis of the sex differences in each study, as well as the integration of all of them, using transcriptomic meta-analysis techniques.

In the selection of the studies, the standards of the Prisma guide were applied to carry out systematic reviews. Seven studies with a total of 267 samples (132 controls and 135 PD cases) were identified. Transcriptomic data from three relevant brain tissues: the frontal cortex, the striatum, and the substantia nigra were then processed and bioinformatically analyzed. Lastly, the differential patterns of expression were meta-analyzed to define a consensus pattern in PD, by sex.

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Of the 237 differentially expressed genes in the substantia nigra, 75 and 162 were significantly increased in males and females, respectively. In summary, García-García comments, “male patients with PD present alterations in the pathways related to oxidative stress, inflammation, and the innate immune response, which represent hallmarks of neurodegeneration.”

Among the altered characteristics in female patients with PD, “the importance of acidification, microtubule stability, mitochondrial and lysosomal dysfunction, glutamic metabolism, and neurotoxicity for neurodegeneration and neuronal death in PD” stand out.

Variations by sex

Among the gene families with higher expression in the substantia nigra of female patients were identified: secretogranins (SCG2, SCG3, SCG5, and CHGB); V-ATPase subunits-ATP5B, ATP6AP1, ATP6V0D, ATP6V1B2, ATP6V1E1, and ATP6V1G2; TIM22 complex subunits; axonal transport and stability of the cytoskeleton; mitochondrial porins-VDAC2 and VDAC3; glutamic-oxaloacetic transaminase-cytoplasmic and mitochondrial forms GOT1 and GOT2; and serine/threonine phosphatase subunits-PPP3CB and PPP2CA.

For male PD patients: metallothioneins, which include genes such as MT2A, MT1E, and MT1M; apolipoproteins-APOL1 and APOC2; and transmembrane proteins induced by interferon-IFITM2 and IFITM3.

Regarding whether the results were as expected or not, the researcher points out that “an important group of results in this work had been linked to other neuronal, intellectual and cognitive disorders. In particular, some specific genes have previously been associated with PD, which “confirms the robustness of the computational strategy applied.”

But there is also a new group of genes not yet associated with this pathology. “Further exploration of these genes may open new perspectives for biomarker identification, early diagnosis, and therapeutic approaches in PD and related disorders,” he notes.

García-García has indicated that “the identification of new biomarkers of this disease, which specifically take gender into account, will allow progress in the development and application of personalized medicine, to favor precision in diagnoses and prognoses”.

cellular atlas

The next steps in this research will be focused on generating an atlas that describes in detail, by cell type, the reason for these sex differences in PD. To do this, “single cell and spatial transcriptomic studies will be used, which will provide very specific and very useful information on this disease.”

Likewise, sex differences will be investigated in the microbiome and also through radiomic analysis of medical images. “This set of results and developed methodologies will favor studies on gender differences and will enable better and more specific interventions in the treatment of PD.” Enrique Mezquida

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