Neurodegenerative disorders reversed by ATP13A2 flipping sphingomyelin across lysosome

Neurodegenerative disorders involve ATP13A2 gene mutations in Parkinson’s disease (PD), Kufor-Rakeb syndrome (KRS), spastic paraplegia (SPG), neuronal ceroid lipofuscinosis (NCL), and amyotrophic lateral sclerosis (ALS). Here, we report that the P-type ATPase transporter ATP13A2 (PARK9) transports sphingomyelin (SM) across the lysosomal membrane for recycling to the cell membrane, by an ATP hydrolysis-dependent transbilayer flip-flop mechanism. ATP13A2 inactivation induces SM lysosomal storage disorder (smLSD). Sustained smLSD triggers glycosphingolipid catabolism with neuronal SM insufficiency, ceramide spillover, and autofluorescent ceroid lipofuscins in mice, recapitulating clinical ATP13A2 mutation-caused impulsive behaviour and movement disorders. Drug screening identifies that FTY720 (fingolimod) inhibits sphingomyelinase cleaving SM to ceramide, reversing ATP13A2 knockout-induced SM shortfall, ceramide accumulation, monoaminergic neurotransmission defect and motor paralysis. These findings demonstrate that ATP13A2 is a SM flippase, smLSD underpins neurodegeneration, and inhibiting sphingomyelin/ceramide imbalance attenuates neurodegenerative disorders with ATP13A2 mutation, providing a framework for prophylactic/therapeutic interventions in PD-ICD, KRS, SPG, NCL, and ALS.