Implementation of human neuronal cultures and mouse models of Pantothenate kinase 2 deficiency to investigate pathogenic mechanisms of iron-related neurodegeneration and evaluate Coenzyme A therapeutic efficacy

The neurodegeneration associated with defects in Pantothenate Kinase-2 (PKAN) and coenzyme A (CoA) synthase (COPAN) are disorders belonging to the group of neurodegenerative diseases with iron accumulation (NBIA), both resulting in defects in the synthesis of CoA, and for which there is no cure. A typical feature of the diseases is a massive accumulation of the metal in specific brain regions (called basal ganglia). CoA is an essential molecule for the functioning of many metabolic pathways. To date, it is not yet clear how these alterations may lead to the accumulation of brain iron and what is the role of the metal in the diseases. Our data, obtained on neuronal cells derived from patient fibroblasts and on mouse model, indicate that they are suffering from several defects in mitochondria (cellular organelles essential for energy production), which can be partially corrected by CoA treatment. These defects involve both the mitochondrial iron management and the production of energy, crucial functions for the preservation of neuronal cells. In this project we plan to investigate the molecular mechanisms leading to the disease using more complex cell and animal models (PKAN and COPAN), which more faithfully recapitulate the human pathological conditions. We will develop subtypes of human neuronal cells and mouse models altered in both genes (PANK2 and COASY). These new models are essential both for the understanding of disease processes and for testing the therapeutic efficacy of CoA. The main goal is to obtain pre-clinical data necessary to evaluate the use of CoA in the treatment of these diseases.