Submitted Abstract
Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder worldwide, is mainly characterized by degeneration of the nigrostriatal pathway. Loss of striatal dopaminergic fibers precedes the degeneration of dopaminergic cell bodies in the substantia nigra (axonal dying back hypothesis). Mitochondria are crucial to fulfill the dopaminergic neuron’s high energetic demands. Indeed, mitochondrial damages are among the shared features of monogenic and sporadic PD. Pathogenic PD genes, including PINK1, Parkin or LRRK2 cause neurodegeneration through mitochondrial impairment and reactive oxygen species (ROS) production. Interestingly, the RhoT1 protein, an essential element of the mitochondrial motor/adaptor complex, is a common element of their pathways. RhoT1 functions as a regulator of mitochondrial mobility, fission/fusion mechanisms, and mitophagy. As so, unveil the RhoT1 role in mitochondrial (dys)function and consequent neurodegeneration is key to better understand PD onset and progression. To shed light on the mechanisms behind the axonal degeneration that precedes dopaminergic cell death, we aim to unveil if there is a threshold of mitochondrial damage that can be tolerated by the distal axons of dopaminergic neurons before they initiate a rapid degeneration process. Particularly, we will unveil the influence of RhoT1 mutations (p.R272Q and p.R450C) in mitochondrial dysfunction and their effect on dopaminergic neuronal loss. For that, patient-specific induced pluripotent stem cells (iPSCs)-derived midbrain organoids will be used. Therefore, this project will contribute to a better characterization of the molecular mechanisms behind PD progression leading ultimately to the development of novel and more effective therapeutic strategies against PD.