Neurotoxicity of Spermine Synthase-deficiency and Polyamine Imbalance

精胺合酶缺乏和多胺失衡的神经毒性

• 批准号: 10445331
• 负责人: Rong Grace Zhai
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445331
• 关键词: Affect; Aldehydes; Antioxidants; Autophagocytosis; Biogenesis; Biology; Blood; Bone Marrow; Brain; Brain Injuries; Catabolism; Cells; Data; Disease; Disease Progression; Drosophila genus; Enzymes; Family; Fibroblasts; Functional disorder; Gene Library; Genes; Genetic; Genetic Diseases; Glutathione S-Transferase; Goals; Human; Hydrogen Peroxide; Hypoxia; Image; Intervention; Ischemic Brain Injury; Life; Lysosomes; Membrane; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Mutation; Nervous system structure; Neurologic Symptoms; Neurons; Online Mendelian Inheritance In Man; Outcome; Oxidation-Reduction; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Polyamine Catabolism; Polyamines; Proteins; Putrescine; Reactive Oxygen Species; Role; Skin; Snyder-Robinson syndrome; Spermidine; Spermine; Spermine Synthase; Stroke; Stromal Cells; Survival Rate; Synapses; Syndrome; Testing; Tissues; Toxic effect; Traumatic Brain Injury; Work; X-linked intellectual disability; aldehyde dehydrogenases; biobank; bone; causal variant; cell type; cellular pathology; efficacy evaluation; in vivo; inhibitor; insight; lymphoblast; metabolic profile; mutant; nervous system disorder; neuropathology; neurotoxicity; oxidation; polycation; response; trafficking; transcriptomics

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.

精胺合酶缺乏与多胺失衡的神经毒性 项目总结 多胺，即亚精胺、精胺及其前体腐胺受到严格控制 生命所必需的聚阳离子。观察到多胺代谢的失调伴随着几个 神经系统疾病包括缺氧性和缺血性脑损伤。然而，病态的 神经系统中多胺失衡的后果尚不清楚。多胺的关键作用 最近，随着Snyder-Robinson因果突变图谱的绘制，神经系统中的新陈代谢出现了 智能障碍综合征(RS，OMIM 309583)与精胺合成酶(Sms)有关，Sms是一种催化 亚精胺将亚精胺转化为精胺。SRS是第一个被证实与 多胺代谢途径。SRS的神经学表现提示长期的病理改变 多胺失衡的后果，并提供了一个独特的机会来发现神经系统特有的 短信功能与多胺代谢。我们已经建立了SRS的果蝇模型，并发现 人和果蝇的Sms蛋白在功能上是保守的，果蝇Sms的丢失是概括性的 SRS病理的几个关键特征，包括多胺失衡、存活率降低和突触 功能障碍。我们发现，SMS缺乏会导致精胺分解代谢过度，继而 体内溶酶体功能障碍与氧化应激。我们假设精胺/精胺失衡是由于 缺乏短信会引起多胺分解代谢的改变，并中和有害的代谢产物 多胺分解代谢将改善SRS的表型和疾病进展。在此应用程序中，我们将 丹参体内神经功能表征及多胺神经毒性分析 失衡，研究SRS患者血淋巴母细胞、皮肤成纤维细胞和骨BMSC的细胞表型， 并进一步发现SRS的遗传抑制因子和潜在的药物干预措施。建议数 这项工作将对多胺和SMS的功能提供重要的见解，并描绘出 精胺合成酶缺乏症神经病理基础的神经元机制 对与多胺相关的神经疾病的持续影响。

项目成果

Specific binding of Hsp27 and phosphorylated Tau mitigates abnormal Tau aggregation-induced pathology.

Hsp27 和磷酸化 Tau 的特异性结合可减轻 Tau 聚集引起的异常病理

• DOI: 10.7554/elife.79898
• 发表时间: 2022-09-01
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Zhang, Shengnan;Zhu, Yi;Lu, Jinxia;Liu, Zhenying;Lobato, Amanda G.;Zeng, Wen;Liu, Jiaqi;Qiang, Jiali;Zeng, Shuyi;Zhang, Yaoyang;Liu, Cong;Liu, Jun;He, Zhuohao;Zhai, R. Grace;Li, Dan
• 通讯作者: Li, Dan