Identificação de genes e mecanismos moleculares associados ao desenvolvimento da Doença de Parkinson

Abstract

Parkinson’s Disease (PD) is characterized by progressive loss of dopaminergic neurons in the substantia nigra and accumulation of alpha-synuclein, with motor and non-motor symptoms. The etiology of PD interplay between genetic and environmental factors. The use of some methodologies such Whole Exome Sequencing (WES) and metabolomics has played a prominent role in expanding the mutational spectrum in PD and in understanding its pathophysiology. However, investigations of this nature are still scarce, especially in the Brazilian population. In the present study, we aimed to identify new molecular causes associated with PD (approach 1) and identify metabolic pathways of development and/or progression of PD (approach 2). For approach 1, we will analyze 10 individuals with early-onset PD (<30 years) using WES. For approach 2, we will analyze by Nuclear Magnetic Resonance the metabolic profile (urine, plasma, and saliva) of two groups of PD patients (Carriers of variants in the LRRK2/GBA/PRKN genes and patients with idiopathic PD) compared to elderly healthy people, the results obtained were subsequently used in enrichment analyzes. WES results pointed to 12 variants (genes PRKN, GBA, SYNJ1, EIF4G1, UCHL1, SLC35G2, NOTCH3, CSF1R, BAP1, and TWNK) in 9 patients. In the metabolomics approach, evidence in arginine metabolism, urea cycle, energetic metabolism, microbiota, and glutamate metabolism. Our enrichment analyzes pointed to 14 genes: MAPT, SNCA, PRKN, GBA2, RERE, KCNN3, MAP3K14, CAMK2D, GCH1, GPR65, CTSB, CARS2, SLC38A1 and GFPT2. We believe that the results obtained in this study can contribute to a better characterization of mechanisms underlying PD and can be used as a basis for strategies for early diagnosis, prognosis and differentiated therapy in our population.