ABSTRACT Parkinson’s disease is an umbrella of different subtypes that manifest with distinct clinical features and different underlying pathogenic mechanisms. Genetics, inflammation, and accumulation of alpha-synuclein are the main pathogenic drivers of the disease, playing a different role in sub-groups of patients. Stratifying patients based on the main pathogenic mechanisms is becoming key in the scenario of precision medicine. Extensive characterization of the role of these pathogenic mechanisms in early onset Parkinson’s disease (EOPD) is lacking. EOPD is a rare condition where PD manifests in patients before the age of 50 years and thus affecting large part of the lives of these subjects. Our central hypothesis is that EOPD implies different sub-types of patients with prognostic outcomes related to diverse contribution of genetics, inflammation and alpha-synuclein accumulation in their pathogenesis. The overall objective of this proposal will be to characterize the contribution of genetics, inflammation, and alpha-synuclein accumulation in large cohort of EOPD and assess how these mechanisms can guide the identification of EOPD sub-types. To achieve this objective the main aims of this proposal will focus on 1) characterizing the clinical and genetic profile of a large cohort of EOPD; 2) assessing the presence of alpha-synuclein in central and peripheral biosamples; 3) profiling the central and peripheral inflammatory activation of EODP compared to late onset PD (LOPD) and non-affected subjects (CTRL). For the first aim we will perform a deep phenotypical characterization of a population of EOPD patients and identify phenotypical clusters through an unbiased hierarchical cluster analysis. Subjects will also be profiled genetically through Whole Genome Sequencing (WGS) for the identification of known and new genetic variants, and for burden analysis of rare gene variants. In the second aim we will assess alpha-synuclein amplification assay, one of the most promising innovative biomarkers for synucleinopathy, on skin biopsies and CSF of subjects with EOPD. In the third aim we will characterize the expression profiles of single cells data and an extensive proteomic panel for inflammatory markers from peripheral blood and cerebrospinal fluid of EOPD, LOPD and CTRL, to determine inflammatory activation in EOPD and characterize cell-specific (innate vs adaptive immunity). Finally, we will correlate data from the three aims to assess the profiles of genetics, clinical, inflammatory, and biomarkers data in EOPD sub-types. While most of the current research on this topic focuses on single aspects of the disease, this research proposal is innovative because it correlates different disease mechanisms to detect subtypes of EOPD. The main significance of this project will be to provide new insights in the pathogenesis of EOPD which will be informative to the design of mechanism-driven therapeutic approaches for EOPD, provide useful information for pati...