Stephanie Vrijsen, Laura Besora-Casals, Sarah van Veen, Jeffrey Zielich, Chris Van den Haute, Norin Nabil Hamouda, Christian Fischer, Bart Ghesquière, Ivailo Tournev, Patrizia Agostinis, Veerle Baekelandt, Jan Eggermont, Eric Lambie, Shaun Martin, Peter Vangheluwe
Recessive loss-of-function mutations in ATP13A2 ( PARK9 ) are associated with a spectrum of neurodegenerative disorders, including Parkinson's disease (PD). We recently revealed that the late endo-lysosomal transporter ATP13A2 pumps polyamines like spermine into the cytosol, whereas ATP13A2 dysfunction causes lysosomal polyamine accumulation and rupture. Here, we investigate how ATP13A2 provides protection against mitochondrial toxins such as rotenone, an environmental PD risk factor. Rotenone promoted mitochondrial-generated superoxide (MitoROS), which was exacerbated by ATP13A2 deficiency in SH-SY5Y cells and patient-derived fibroblasts, disturbing mitochondrial functionality and inducing toxicity and cell death...
December 8, 2020: Proceedings of the National Academy of Sciences of the United States of America