Public defence - Chiara Cappelletti

Parkinson´s disease (PD) and multiple sclerosis (MS) are two of the most common complex neurological disorders affecting millions of people worldwide. PD is characterized by the loss of dopaminergic neurons in the midbrain and by the presence of protein aggregates, called Lewy bodies, in many regions of the brain. These pathological hallmarks ultimately cause characteristic motor symptoms and, in later stages of the disease, also cognitive impairment.

MS is an autoimmune disease characterized by chronic inflammation and demyelination in the central nervous system that lead to both cognitive and physical deficits. Therefore, both PD and MS present with debilitating symptoms that negatively affect patients´ life.

Currently, there is no cure for these diseases, only symptomatic treatment, for PD, and disease modifying therapies, for MS are available. This is due to the still poor understanding of the molecular mechanisms causing these diseases. In the last years, the development of novel technologies has enabled whole genome studies and the identification of several genetic variants associated with increased risk of developing complex diseases such as PD or MS. However, the biological mechanisms behind these associations remain to be elucidated. 

A central goal of this thesis has been to perform advanced analyses of omics data, i.e RNA-sequencing and quantitative proteomics, for the identification of biological processes implicated in PD and MS that could ultimately be used as targets for the development of novel disease-modifying therapies. 

By comparing the brain transcriptome of PD patients and neuropathologically healthy donors, we found that gene expression and many related biological processes are highly disease-stage specific, whereas ATP-metabolic processes are involved at all disease stages. Additionally, we linked the expression of MAP4K4 and PHYHIP to genetic and epigenetic factors previously associated with increased risk of PD. 

Further, we showed that brain gene expression and age-related gene expression can be influenced in a sex-specific manner by both known PD variants and newly identified loci manifesting pleiotropy between PD and sex-specific traits. By doing so, we demonstrated that there is a genetic component to the sex difference observed in PD prevalence. 

Next, by investigating the proteome of unstimulated and stimulated CD4+ T cells of MS patients and healthy controls, we showed dysregulation in T cell activation in MS samples and identified the Nur77 signaling pathway as potential target for future studies. 

Collectively, the work presented in this thesis comprises a wide range of analytical methods that permitted the identification of genes, proteins and biological processes involved in PD and MS, but the same analyses methods could be used to study other complex diseases. Furthermore, our studies have identified several genes and biological pathways that could be prioritized in future functional studies enabling a deeper understanding of the molecular mechanisms causing PD and MS and ultimately leading to improved therapeutic options for the patients.