Effects of miRNAs secreted by extracellular vesicles on dopaminergic neuron specification in cellular (2D/3D) models of Parkinson's disease

• Grant number: 24/15190-4
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: April 01, 2025
• End date: March 31, 2029
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Marilene Hohmuth Lopes
• Grantee: Martha Liliana Medina Solano
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/15557-4 - Prion protein and its partners: emerging targets for glioblastoma stem cell based-therapy, AP.JP2

Abstract

Parkinson's disease (PD) is the second most prevalent progressive neurodegenerative disease in the world, affecting approximately 10 million people globally. With no known cure, the management of PD still faces substantial challenges in both diagnosis and treatment. The disease is characterized by the death of dopaminergic neurons in the midbrain, resulting in significant motor and cognitive alterations. Although the exact cause remains elusive, the literature suggests that PD may result from a combination of genetic and environmental factors, which affect cellular homeostasis and increase oxidative stress, neuroinflammation, and the inappropriate accumulation of proteins, such as alfa-synuclein, in dopaminergic neurons. Despite advances, the molecular pathways involved in PD are still not fully understood, and the identification of key molecules for diagnosis and prognosis remains a crucial challenge. In this scenario, the study of the secretome profile of affected cells has stood out. In particular, microRNAs (miRNAs), key molecules in the regulation of post-transcriptional gene expression present in extracellular vesicles (EVs), have been shown to play a crucial role in intercellular communication during disease progression. Recently, our group identified that miRNAs enriched in EVs during dopaminergic differentiation from neural precursors are associated with PD biology. However, the role of these miRNAs in robust models of dopaminergic origin exposed to neurotoxins in vitro has not yet been elucidated. Therefore, this study aims to investigate the function of miRNAs derived from EVs of dopaminergic neurons, obtained through differentiation of the SH-SY5Y cell line and mesencephalic organoids, in in vitro models of PD. We will use 2D and 3D platforms, including neuronal lines and brain organoids derived from induced pluripotent stem cells (iPSCs), which recapitulate the structural features of the midbrain substantia nigra. Our goal is to modulate the expression of miRNAs of interest through agomirs and antagomirs, which mimic and inhibit miRNAs, respectively. We will focus on analyzing the expression profile of these miRNAs, their mechanisms of action and their possible neuroprotective functions. This research has the potential to provide new insights in the identification of biomarkers that can significantly improve the prediction, diagnosis and treatment of PD, with important implications for future clinical application.