Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance

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Neurotoxicity of Spermine Synthase-Deficiency and Polyamine Imbalance PROJECT SUMMARY Polyamines, namely spermidine, spermine, and their precursor putrescine are tightly regulated polycations essential for life. Dysregulation of polyamine metabolism has been observed to accompany several neurological disease conditions include hypoxic and ischemic brain damage. However, the pathological consequence of polyamine imbalance in the nervous system remains unclear. The pivotal role of polyamine metabolism in the nervous system recently emerged with the mapping of causal mutation of Snyder-Robinson Intellectual Disability Syndrome (SRS, OMIM 309583) to spermine synthase (SMS), an enzyme that catalyzes the conversion of spermidine to spermine. SRS is the first confirmed genetic disorder associated with the polyamine metabolic pathway. Neurological manifestations in SRS indicate the long-term pathological consequence of polyamine imbalance, and provide a unique opportunity to uncover nervous system-specific function of SMS and polyamine metabolism. We have established a Drosophila model for SRS and found that human and Drosophila SMS proteins are functionally conserved, and loss of SMS in Drosophila recapitulated several key features of SRS pathology, including polyamine imbalance, reduced survival rate, and synaptic dysfunction. We discovered that SMS deficiency leads to excessive spermidine catabolism, and consequent lysosomal dysfunction and oxidative stress in vivo. We hypothesize that spermidine/spermine imbalance due to SMS deficiency causes altered polyamine catabolism, and that neutralizing the detrimental metabolites from polyamine catabolism will ameliorate phenotypes and disease progression in SRS. In this application, we will characterize the neuronal function of SMS in vivo, analyze the neurotoxicity resulted from polyamine imbalance, study cellular phenotypes in SRS patient blood lymphoblast, skin fibroblast and bone BMSC cells, and further discover genetic suppressors and potential pharmacological interventions for SRS. The proposed work will provide significant and important insights into the function of polyamines and SMS, and delineate the neuronal mechanisms underlying the neuropathology of spermine synthase-deficiency, and have long-lasting and sustained impact on polyamine-associated neurological disorders.