Spermine synthase deficiency causes lysosomal dysfunction and oxidative stress in models of Snyder-Robinson syndrome

Polyaminesare tightly regulated polycations that are essential for life. Loss-of-function mutations in spermine synthase(SMS), a polyaminebiosynthesis enzyme, cause Snyder-Robinson syndrome(SRS), an X-linked intellectual disabilitysyndrome; however, little is known about the neuropathogenesis of the disease. Here we show that loss of dSms in Drosophila recapitulates the pathological polyamineimbalance of SRS and causes survival defects and synaptic degeneration. SMS deficiency leads to excessive spermidinecatabolism, which generates toxic metabolites that cause lysosomal defects and oxidative stress. Consequently, autophagy–lysosome flux and mitochondrial function are compromised in the Drosophila nervous system and SRS patient cells. Importantly, oxidative stress caused by loss of SMS is suppressed by genetically or pharmacologically enhanced antioxidant activity. Our findings uncover some of the mechanisms underlying the pathological consequences of abnormal polyaminemetabolism in the nervous system and may provide potential therapeutic targets for treating SRS and other polyamine-associated neurological disorders.