Exploit iron-burden astrocytes and mouse models to define the therapy for PKAN and CoPAN.

PKAN and CoPAN can be considered paradigmatic neurodegenerative disorders characterized by CoA deficiency, mitochondrial dysfunction, iron accumulation, and oxidative stress. Despite extensive research, the knowledge on the mechanistic details leading to neurodegenerative process in these disorders is still lacking, essentially for the absence of disease models that recapitulate the human phenotype, characterized by brain iron deposition. We have obtained a cellular model recapitulating the human phenotype and thus we have now the opportunity to use it, not only to study the pathogenic mechanism, but also to verify the efficacy of previously identified therapeutic compounds. We obtained very promising preliminary results suggesting the efficacy of CoA and 4-PBA treatments in alleviate aberrant processes in human cellular models. If these data will also be confirmed in vivo in mouse models, they will represent relevant opportunity for setting new protocols to be proposed for pre-clinical and clinical experimentation. We think that the results of this project will go far beyond the cure of these two specific diseases. Considering the key role of CoA in cellular metabolism, we expect to shed light on specific pathways involved in the general process of neurodegeneration. This body of knowledge will pave the way to the design of specific therapeutic strategies aimed at preventing or reversing the neurodegenerative process thus impacting on large populations of patients.