Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance

精胺合酶缺乏和多胺失衡的神经毒性 项目摘要 多胺，即亚精胺，精胺，和它们的前体腐胺是严格管制的 生命所必需的聚阳离子。已经观察到多胺代谢的失调伴随着几种 神经疾病病症包括缺氧和缺血性脑损伤。然而，病理 神经系统中多胺失衡的后果仍不清楚。多胺的关键作用 神经系统中的代谢最近出现了Snyder-Robinson因果突变的映射 智力障碍综合征（SRS，OMIM 309583）与精胺合酶（SMS），一种催化 亚精胺向精胺的转化。SRS是第一个被证实的遗传性疾病， 多胺代谢途径SRS的神经系统表现提示SRS的长期病理改变 多胺失衡的后果，并提供了一个独特的机会，揭示神经系统特异性 SMS和多胺代谢的功能。我们建立了一个果蝇SRS模型，发现 人和果蝇的SMS蛋白在功能上是保守的，并且在果蝇中的SMS的丢失被再现。 SRS病理学的几个关键特征，包括多胺失衡、存活率降低和突触 功能障碍我们发现，SMS缺乏导致过量的亚精胺催化剂， 体内溶酶体功能障碍和氧化应激。我们假设亚精胺/精胺失衡是由于 SMS缺乏导致改变的多胺催化剂，中和有害的代谢物， 多胺催化剂将改善SRS的表型和疾病进展。在这个应用程序中，我们将 在体内研究SMS的神经功能，分析多胺的神经毒性 研究SRS患者血液淋巴母细胞、皮肤成纤维细胞和骨BMSC细胞中细胞表型， 并进一步发现SRS的遗传抑制因子和潜在的药物干预。拟议 这项工作将为多胺和SMS的功能提供重要而重要的见解，并描绘出 精胺脱氢酶缺乏的神经病理学基础的神经机制，并具有长期的 和对多胺相关神经系统疾病的持续影响。

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.