Age- and sex-specific alterations in the midbrain of a Parkinson disease mouse model.

Clinical diagnosis of Parkinson´s disease (PD) relies on the presence of motor symptoms, although
non-motor symptoms can manifest themselves already up to 20 years earlier. Dissecting molecular
changes occurring in the prodromal stages of the disease could facilitate earlier and more accurate
diagnosis. It is being investigated the gene expression signatures and chromatin profiles during aging
of in vivo midbrain sections and isolated nuclei of different cell types from a knock-out mouse model
for Park7, a frequently mutated gene in early-onset PD. This process includes RNA and nuclei
extraction for bulk RNA-seq and snATAC-seq analysis. Through the integrative analysis, we aim to
identify the upstream regulatory events and key transcription factors controlling the pathogenic gene
expression changes at the chromatin level. We have observed a robust age and sex-dependent
transcriptomic deregulation in the midbrain of Park7/- mice. These changes are stronger in males,
what correlates with the higher prevalence and worsen symptoms of PD in men. After performing an
enrichment analysis, we can see that estrogen and retinoic acid appear enriched as potential
regulators in the midbrain of Park7/- male mice. In females, their default higher levels of estrogen
could act as protectant. Cyp1b1 gene expression downregulation, an enzyme involved in the
production of both estrogen and retinoic acid, seems to be a central event in the higher
transcriptional deregulation of Park7/- male mice. These results were validated by RTqPCR, which
also reveals they are region-specific, since they don´t appear in other brain regions. Our findings
pointing out astrocytes, a cell population providing support to the dopaminergic neurons and
protecting them against oxidative stress, seem to be quite relevant in comparison to microglia,
another cell population supporting the neurons against oxidative stress. In addition, some of these
changes can be observed in mouse primary astrocytes after performing knock down treatments.
Further experiments to validate the upstream regulators and identify pathways are currently in
Keywords: Epigenetics, Parkinson’s disease, DJ1, mouse model

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