Pathway analysis of this interacton suggested several primary targets of a-synuclein, with the glycosphingolipid biosynthesis and the protein ubiquitination pathways being common to the miRNome IPA analysis. Data mining of these pathways in three GWAS studies highlighted the consistent associations of USP37 and ST8SIA4 with PD and gave further support to the involvement of glycosphingolipids and the ubiquitin proteasome system in the physiopathology of PD. Furthermore, 3 miRNAs which are among the most abundant miRNAs in primary human neuronal and glial cells and simultaneously involved in the regulation of a-synuclein interacting genes, emerged as the main modulators of these two pathways in our expression analyses.Glycosphingolipids and their sialic acid-containing derivatives��gangliosides, are important cellular components and abundant in the nervous system. They are known to undergo Abmole GSK1120212 dramatic changes during brain development, but our knowledge on the mechanisms underlying their quantitative and qualitative changes is still fragmentary . Glycosphingolipids are closely related to the ceramide metabolism that has already been linked to PD through the 194413-58-6 glucocerebrosidase gene . In addition to being the major non-lysosymal system for degrading proteins in the cell, the ubiquitin proteasome system regulates function and translocation of proteins, many of which play a role in the determination of cell fate. Protein mediators of apoptosis are regulated by the UPS, via direct or indirect modulation of proteins associated with cell death. Mutations in two PD genes, the E3-ligase Parkin and the deubiquitinating enzyme UCHL1, may lead to a susceptibility to UPS failure resulting in protein accumulation, Lewy body formation and dopaminergic cell death. Furthermore, dysfunctional a-synuclein and a-synuclein oligomeric species have also been implicated in the impairment of the proteasome system , which in turn has been implicated in a-synuclein turnover . Several ubiquitin specific proteases have been consistently associated with PD . To our knowledge, this is the first global miRNAs expression analysis performed in PBMCs in a relatively large cohort of PD patients and controls.