INTEGRATED GENOMIC ANALYSIS OF ISOLATED CD14+ MONOCYTES IN PATIENTS WITH GBA-RELATED PARKINSON¿S DISEASE

Background: Genetic mutations of the gene encoding for the beta- glucocerebrosidase (GCase), GBA gene, represent the major genetic risk factor for Parkinson’s disease (PD). The pathogenic mechanisms associated with these mutations and modifiers responsible for the reduced penetrance of this gene are not fully elucidated yet. However, the function of the GBA gene is at the crossroad between the endo-lysosomal pathway and the immune response, which are two main mechanisms involved in PD pathogenesis. Aim: With the present work we aim to characterize the clinical features of a population of patients with PD and healthy controls (CTRL) with and without mutations of the GBA gene and characterize the transcriptomic profiles of purified CD14+ monocytes in order to identify 1) pathogenic mechanisms associated with GBA- PD; 2) potential biomarkers for earlier detection of GBA mutation carriers who will phenoconvert to a disease status; 3) new therapeutic targets for precision medicine approaches. Material and methods: PD patients and CTRL were enrolled at the Fresco Institute (NYU Langone Health, NY) and Mount Sinai School of Medicine (NY). Demographic information, clinical and family history, as well as motor and non-motor symptoms of PD were collected. DNA and RNA from purified CD14+ monocytes, plasma and peripheral blood mononuclear cells (PBMC) were collected. Genotyping (Illumina Global Screening Array with custom Neurodegenerative disease panel) and RNAseq analysis (60M ribo- depleted, paired-end reads) was performed. Data were analyzed through integrative genomic analysis leveraging different computational methods (differential expression, nested interaction model, outlier detection and trans-eQTLs). Results: Statistical analysis comparing the clinical phenotypes of 19 PD/GBA+, 37 PD/GBA-, 37 CTRL/GBA-, 9 CTRL/GBA+ showed increased non-motor symptoms in CTRL/GBA+ and increased family history and cognitive impairment in the PD/GBA+ cohort. Integrative genomic analysis of a cohort of 56 PD/GBA-, 66 CTRL/GBA-, 23 PD/GBA+, and 13 CTRL/GBA+ identified a large number of differentially expressed genes and deregulated pathways in the PD/GBA+ compared to CTRL/GBA+ as well as PD/GBA- groups. In particular, PD/GBA+ showed deregulated alpha-synuclein-, amyloid- and aging-related processes compared to PD/GBA-. Compared to CTRL/GBA+, in manifesting carriers there was a deregulation of all the major pathogenic pathways previously associated with PD. Outliers and trans-eQTLs analysis confirmed a prominent involvement of lysosomal, membrane trafficking, and mitochondrial targets, identifying also additional related genes. Discussion: Clinical and demographic analysis of PD patients and CTRL with and without GBA mutations highlighted characteristic features in the PD/GBA+ and CTRL/GBA+ cohort. Genomic analysis of isolated CD14+ monocytes identified specific molecular targets and deregulated pathways that can help understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.