Submitted Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder, which has currently no cure. Mutations in the gene encoding for the leucine-rich-repeat-kinase-2 (LRRK2) protein, especially the G2019S, have been identified as a cause for the development of the familial form of the pathology. However, despite extensive investigations, the molecular signature causing the dopaminergic degeneration remains elusive. In this project, we aim at elucidating the potential interaction between LRRK2-G2019S and the transcription factor NR2F1. Our preliminary data showed that NR2F1 transcript is significantly downregulated in dopaminergic neurons and midbrain organoids derived from PD patients carrying the mutation compared to healthy controls. The correction of the mutation via gene editing restores NR2F1 mRNA levels back to healthy control levels. In the same models, NR2F1 downregulation is accompanied by mitochondrial morphological alterations and dopaminergic degeneration. To validate the pathological relevance of the link between NR2F1 and LRRK2-G2019S we will investigate whether the two proteins are directly interacting. We will also modulate NR2F1 levels to prove its essential role in the occurrence of the mitochondrial and dopaminergic phenotypes. Furthermore, we will identify small molecules modulating NR2F1 activity via in silico analysis to later validate their potential rescue effect in microfluidic devices compatible with high-content imaging screening.The obtained data will allow us to identify the role of NR2F1 in PD and establish whether its modulation can represent a therapeutic option.