CLINICAL AND BIOCHEMICAL SIGNATURES OF GBA-RELATED PARKINSON DISEASE

Background: Parkinson’s disease (PD) is a common neurodegenerative disorder mainly characterized by dopaminergic neuronal loss in the substantia nigra and α-synuclein protein aggregation. Genetic factors are well known to contribute to PD susceptibility. Mutations in the glucocerebrosidase (GBA) gene are the commonest genetic risk factor for PD and also impact on disease development and progression. A better clinical and genetic classification of patients, as well as the identification of clinical and biochemical markers are therefore of utmost importance for multifold reasons: - to improve the characterization of patient's clinical phenotype of different forms of PD; - to identify reliable biomarkers for genetic subtypes of PD in order to obtain and early diagnosis and monitor disease progression; - to include patients with specific mutations in ad hoc clinical trials aiming to tailor medical treatment. Objective: The present project aims at exploring the bases of PD phenotype through the correlation of specific genetic and biochemical findings with the clinical picture, in subjects with GBA-related PD (GBA-PD) and subjects affected by idiopathic PD (non-mutated PD – NM-PD). We divided the investigation in three studies: i) definition of a clinical and biochemical profile which could distinguish GBA-PD from non-mutated PD (NM-PD) (study I); ii) longitudinal evaluation of the disease course of GBA-PD compared to NM-PD along 2-year follow-up, with a focus on clinical and biochemical parameters (study II); iii) definition of a biochemical prodomal profile in the asymptomatic GBA carriers that could differentiate subjects more at risk to develop PD. Methods: a comprehensive clinical assessment of motor and non-motor symptoms alongside the analysis of α-synuclein levels, glucocerebrosidase (GCase) enzymatic activity and main GCase-related lysosomal proteins in peripheral blood mononuclear cells (PBMCs) were performed in all the three studies. Results: At baseline, GBA-PD showed a worse clinical outcome both on motor and non-motor features compared to NM-PD, as well a distinctive biochemical profile in PBMCs showing significantly higher α –synuclein levels, lower GCase activity, higher LIMP-2 and lower Saposin C levels. Over time, both the GBA-PD and the NM-PD groups separately displayed a significant deterioration in dysautonomic functions, motor performance, cognitive functions and mood disorder compared to baseline, while GBA-PD had a more severe motor progression with a higher disease severity compared to NM-PD. At 2-year follow-up, the level of α-synuclein in PBMCs was able to differentiate GBA-PD from NM-PD and HC. Finally, a unique biochemical profile was observed also in the asymptomatic GBA mutation carriers, in which the combination of higher level of α-synuclein with lower Gcase activity was able to define a malignant prodromal profile. Conclusion: These studies contribute to our current understanding of the role of GBA mutations in the development and progression of PD. We confirm the biological effect of GBA mutations in determining clinical and biochemical distinctive profile of PD. We propose essays in PBMCs as an easily accessible and manageable model to provide a characteristic biochemical profile of GBA carriers, potentially useful for patient stratification or selection in clinical trials.