READING THROUGH THE BUILDING BLOCKS OF THE GENOME: EXONIC VARIATION IN PARKINSON'S DISEASE

Parkinson's disease (PD) is one of the most common movement disorders worldwide, characterized by a profound and selective loss of dopaminergic neurons in the substantia nigra pars compacta. Treatments aimed at compensating dopamine deficit can alleviate the major motor symptoms and enhance the patients quality of life, but finally are not able to halt or slow down disease progression. Therefore, there is an urgent need to better understand the molecular mechanisms underlying the physiopathology of PD and to identify new biomarkers and new therapeutic targets. The hypothesis addressed in this PhD thesis aims to decipher the structural variability of exonic regions in PD-linked genes and in their relative mRNA transcripts, in order to investigate if these perturbations have some effects on PD pathogenesis. Two major cellular events able to trigger exonic variations in both DNA and mRNA molecules will be examined: copy number variations and alternative splicing. Both mechanisms are well known to play a crucial role in PD onset and can modulate disease severity. An improved comprehension of exonic variability at both genomic and transcriptomic level may prompt new insights to understand the missing heritability and the variety of phenotypic outcomes in PD patients.