SYNERGIZE-PD: Revelando a dinâmica e sinergia da Argonauta-2 e dos miRNAs para o desenvolvimento de terapias inovadoras para a doença de Parkinson.

CHALLENGE: PD therapy is hindered by a lack of early biomarkers and understanding of disease mechanisms. SOLUTION: To address these unmet needs for biomarkers and disease-modifying treatments by identifying common alterations of AGO2 and specific miRNAs in human blood and CSF from PD patients to further develop innovative therapeutic solutions. Experts in clinical and translational medicine, preclinical models, iPSC modeling and in silico, were brought together to integrate distinct methods and disciplines to achieve the main goal. Non-academic members/consultants bring expertise to develop a product-oriented approach. Three RESEARCH OBJECTIVES (RO) were defined to achieve the main aim: RO1: Establish the profile of AGO2 and AGO2-bound miRNAs in distinct stages of PD (Tasks 1, 2) OVERVIEW: Curative therapy for PD is lacking, due to incomplete understanding of disease mechanisms and a lack of druggable targets. Despite some evidence suggesting deregulation of AGO2 and miRNAs in PD; the extent and disease stage at which alterations occur remains unknown. PROGRESS: Blood plasma and CSF from PD patients (idiopathic, genetic) will be collected (Task 1) to assess the profile of AGO2 and bound-miRNAs by performing AGO2 immunoprecitation followed by small RNA seq (Task 2). We aim assessing AGO2/AGO2:miRNA expression and identify key downregulated bioactive miRNAs influencing PD progression for further analysis in RO2. Identifying biomarkers at preclinical or early clinical stage will allow efficient early interventions able to slow down disease progression. RO2: Unveil commonly dysregulated miRNA mechanisms related to neuroprotection (Task 3) OVERVIEW: Posttranscriptional mechanisms impact PD, but previous studies focus on individual validated miRNAs not bound to AGO2 or single pathology endpoints. A comprehensive evaluation of posttranslational modifications regulating neuronal survival pathways is lacking, hindering a global understanding of disrupted pathways. PROGRESS: State-of-the-art technology will be used to uncover posttranscriptional modifications associated with shared signaling pathways in neuronal survival/dysfunction. We expect to identify and preclinically test new druggable targets, which will be addressed in RO3. RO3: Validate AGO2/AGO2:miRNA complexes as drug targets for PD (Tasks 4, 5, 6) OVERVIEW: Current therapies treat PD symptoms only, and are far from ideal; hence, there is an urgent need to test novel disease-modifying therapeutic targets. PROGRESS: First, the impact of AGO2/AGO2:miRNA in neuronal internalization and survival will be tested in a human cell line (Task 4). Then, intranasal delivery of AGO2/AGO2:miRNA in a PD preclinical model will validate the ability of this disease-modifying target to reduce/ameliorate pathogenesis and motor behavior (Task 5). Lastly, PD patient-specific iPSC-derived DAn will be used to validate the ability of AGO2/AGO2:miRNA to rescue the PD phenotype (Task 6). The proposal aims to advance translational research for developing a novel PD treatment, building on our prior research and expertise across disciplines. SYNERGIZE-PD will contribute to creating novel scientific and technological knowledge on the posttranscriptional regulation mediated by AGO2 and bound bioactive miRNAs and uncover its therapeutic value in PD. The team aims to devise a sustainable collaboration strategy beyond the SYNERGIZE-PD project, fostering continued advancement within the field.