Dysregulated Frataxin processing in the pathogenesis of PITRM1-dependent spinocerebellar ataxia

We have recently found that mutations in PITRM1 are associated with a progressive spinocerebellar ataxia syndrome. PITRM1 is a mitochondrial matrix enzyme that digests the mitochondrial fraction of Aβ1-42 and the leader peptide that targets proteins to the mitochondria (called MTS), the powerhouses of the cell. During the import process, the leader peptide is cleaved off by the mitochondrial processing peptidase (MPP) and degraded by PITRM1 in collaboration with the mitochondrial isoform of a second peptidase, the so-called Insulin Degrading Enzyme (IDE). The accumulation of undigested MTS damages the mitochondria and inhibits MPP activity thus impairing processing and maturation of imported proteins including Frataxin, responsible of Friedreich Ataxia. This project will explore the role of dysfunctional Frataxin processing in the SCA syndrome associated with non-sense mutations in Pitrm1 mutant cells and mice. In particular, we will test if approaches aimed at increasing the available levels of mature FXN can prevent mitochondrial dysfunction and thus the onset of ataxia. To this end, we will use pharmacological approaches to activate IDE in cellular models of the disease. Further we will test whether AAV-based gene augmentation in vivo can prevent the ataxic phenotype.