Multi-omics analysis of human brain tissue and an animal model of Parkinson’s Disease

Abstract

Parkinson’s Disease (PD) is the second most prevalent and fastest-growing neurological disorder. The number of affected individuals is expected to double in the next 20 years. The exact molecular mechanisms underlying PD pathology are not completely understood. In addition, its diagnosis mainly relies on clinical criteria related to the characteristic motor dysfunction in PD. Since the symptoms only start to appear at advanced stages of the nigrostriatal degeneration characteristic in PD, there is a strong limitation for the promotion of therapeutic strategies that might be able to change the course of the disease. Allied to that, the limited regenerative capabilities of cells in the CNS complicate the development of restorative treatments. Therefore, understanding the key pathogenetic mechanisms of PD is fundamental for the the development of disease-modifying therapies. Profiling the expression of molecular element such as miRNAs, transcripts and proteins in brains affected by PD might reveal a series of pathological events taking place both at cellular and systemic levels in the course of the disease. The present doctoral thesis aimed to analyze midbrain tissue samples from a cohort of PD patients and controls in a multi-omics set of experiments, looking into the genetic background of the selected subjects, as well as characterizing the expression patterns of miRNAs, transcripts and proteins on those samples. Here, several levels of deregulation were identified across multi-omics datasets in human midbrains affected by PD. Important players and molecular networks that seem to be relevant for advanced stages of PD pathology were revealed: we showed that a marked inflammation and immune response activation takes place in the analyzed midbrains, in addition to defects in protein degradation and metabolic dysfunctions. Our data thus strongly suggest that neuroinflammation may be a veritable therapeutic target, at least in advanced stages of the disease. In addition, we identified not only deregulated transcripts and proteins linked with pathological processes, but also miRNAs that might be involved in the pathophysiology of the disease. Finally, we have also assessed the validity of the prnp. αSyn.A53T mouse model of PD in terms of the overlap in miRNA and mRNA expression with human pathology. A number of correlating results were identified in our longitudinal animal study, providing insight into the time course of pathological changes in the animal brains upon aging that are similar to the ones occurring in human PD patients.