Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia

Abstract Peroxiredoxin 3 (PRDX3) belongs to a superfamily of peroxidases that function as protective antioxidant enzymes. Among the six isoforms (PRDX1–PRDX6), PRDX3 is only protein exclusively localized mitochondria, which are main source reactive oxygen species. Excessive levels species harmful cells, inducing mitochondrial dysfunction, DNA damage, lipid and oxidation ultimately apoptosis. Neuronal cell damage induced by oxidative stress has been associated with numerous neurodegenerative disorders including Alzheimer’s Parkinson’s diseases. Leveraging large aggregation genomic ataxia datasets from PREPARE (Preparing for Therapies in Autosomal Recessive Ataxias) network, we identified recessive mutations genetic cause cerebellar five unrelated families, providing further evidence pathogenesis neurodegeneration. The clinical presentation individuals consists mild-to-moderate progressive concomitant hyper- hypokinetic movement disorders, severe early-onset atrophy, part olivary brainstem degeneration. Patient fibroblasts showed lack protein, resulting decreased glutathione peroxidase activity maximal respiratory capacity. Moreover, knockdown medulloblastoma cells resulted significantly viability, increased H2O2 susceptibility apoptosis triggered Pan-neuronal pan-glial vivo models Drosophila revealed aberrant locomotor phenotypes reduced survival times upon exposure stress. Our findings reveal central role mitochondria implication disease vulnerability suggest targets future therapeutic approaches.