The role of iron and mitochondria in the pathogenesis of Pantothenate Kinase Associated Neurodegeneration (PKAN): development of new neuronal cellular systems and analysis of a mouse model

Pantothenate kinase associated neurodegeneration (PKAN) is the most frequent among diseases collectively defined as NBIA (neurodegeneration with brain iron accumulation). As of today, the understanding of the role of iron in the development of the disease and the knowledge of the mechanisms leading to its accumulation are very limited. Furthermore, even though Pantothenate-kinase2 (Pank2), the protein altered in PKAN, has a mitochondrial location, the effect of its deficit or malfunctioning on mitochondria activity is far to be clear. Aim of this project is to understand the existing relationship between PANK2 gene, cellular iron balance, and mitochondria functionality with the hope to gain fundamental insight into the pathogenesis of PKAN and for the development of therapeutic approaches. Fundamental starting point of the project are our preliminary results showing that Pank2 deficit causes both an alteration of cellular iron balance and the presence of alteration of mitochondria morphology in patients' fibroblasts. The research project proposes the development of new cellular models of the disease, with a basal phenotype resembling that of neurons affected by the degenerative process. These models will consist of a) neurons derived from reprogramming patients' cells and of stem cells derived from hair follicle; b) human neuroblastoma cell lines in which the PANK2 gene has been interfered. In addition, mitochondrial activity will be analysed also in vivo, in deficient PANK2 KO mice. We will work to 1) define the molecular connection between Pank2 function and iron balance in the neural cells; 2) characterize the role and function of the hepcidin-ferroportin axis in neurons and its relevance to brain iron accumulation; 3) investigate the involvement of mitochondria in the pathogenesis of the disease; 4) asses the efficacy of treatments with iron chelators in our cellular models.