SMPD3

帕金森病（PD）是一种影响中枢神经系统的退行性疾病，在美国大约有100万人受到它的影响，而预计到2042年，全球的患者人数可能会攀升至1290万。作为仅次于阿尔茨海默病的第二大神经退行性疾病，帕金森病主要影响老年人群，在85至89岁年龄段达到发病高峰，并且男性比女性更容易患病。 在临床上，帕金森病患者会经历多种运动和非运动症状，这些症状给他们的日常生活带来了诸多不便。病理特征上，帕金森病表现为黑质区域神经元的丧失，导致纹状体内的多巴胺含量减少，并伴有中脑区域出现的路易小体。 虽然高龄被认为是帕金森病的主要风险因素之一，但生活方式的选择，如饮食习惯，以及环境暴露也同样在疾病的发展过程中扮演了重要角色。在过去十年里，遗传学研究揭示了一些与家族性帕金森病相关的罕见基因突变，并通过大规模全基因组关联研究GWAS）发现了散发性帕金森病的多基因背景。尽管已知的遗传变异解释了大约22%的遗传易感性，但至今为止确认的遗传位点只能解释其中的一小部分。 为了填补这一空白，需要更多的病例研究。此外，理解帕金森病风险变异的功能影响对于确定潜在的治疗目标至关重要。然而，尽管人类遗传学在药物研发中用于识别和验证靶标，但GWAS信号往往不能明确指出致病基因。 蛋白质组学研究可以补充这一不足，因为它能帮助我们了解帕金森病风险变异的功能效应，并可能识别出治疗目标和潜在生物标志物。蛋白质不仅是细胞结构的基础，也是许多调节过程的关键参与者，它们的作用不仅取决于其数量，还包括其相互作用、运输以及翻译后的修饰。因此，蛋白质组学研究具有巨大的潜力，可以作为生物标志物、治疗目标及疾病进程监测的工具。 近期的技术进步使得大规模的人群蛋白质组学研究成为可能，例如英国生物银行制药蛋白质组学项目（UKB-PPP），就为研究基因-蛋白质相互作用提供了新的机会。 图片来源：https://doi.org/10.1038/s41467-024-50718-x 近日，来自美国的研究者们在Nat Commun杂志上发表了题为“Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson's disease”的文章，这项研究通过蛋白质基因组网络分析揭示了帕金森病中的失调机制和潜在的介质，有助于我们更好地理解帕金森病中的基因-蛋白质动态，并为识别与GWAS信号相关的潜在介质提供了范例。 蛋白质基因组网络分析 图片来源：https://doi.org/10.1038/s41467-024-50718-x 在这项研究中，研究者开发了一个三相系统级蛋白质基因组学分析框架来表征疾病相关蛋白质和失调机制。蛋白质基因组学分析确定了577种丰富帕金森病相关途径的蛋白质，如细胞因子受体相互作用和溶酶体功能，以及9种在疾病发病机制中具有潜在作用的蛋白，包括LGALS3、CSNK2A1、SMPD3、STX4、APOA2、PAFAH1B3、LDLR、HSPB1、BRK1。 蛋白质基因组网络分析揭示了帕金森病的失调机制和潜在的介质示意图 图片来源：https://doi.org/10.1038/s41467-024-50718-x 综上所述，通过整合UkB蛋白质基因组数据，研究者们创建了一个网络模型，以描绘基因组-蛋白质组的关系及其相互作用。这种综合方法为理解帕金森病及其他复杂疾病的遗传驱动蛋白破坏提供了一个全面的视角，并为进一步研究这些受影响的蛋白质奠定了基础。 参考文献： Abolfazl Doostparast Torshizi et al. Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson's disease. Nat Commun. 2024 Jul 31;15(1):6430. doi: 10.1038/s41467-024-50718-x. 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！ 点击下方「阅读原文」，前往生物谷官网查询更多生物相关资讯~

*仅供医学专业人士阅读参考神经元内过度磷酸化Tau蛋白积累所导致的神经原纤维缠结，是阿尔茨海默病的主要病理特征之一。 研究表明，异常Tau蛋白可以以游离形式或细胞外囊泡（EV）包裹的形式，在神经元之间传播。目前，靶向游离Tau蛋白的Tau抗体药物临床试验屡屡受挫，尚无临床药物，前段时间我们已经一起讨论过。而通过抑制细胞外囊泡释放来阻止异常Tau在神经元之间扩散的治疗策略，仍有待探索。 近日，美国约翰霍普金斯大学医学院的Norman J. Haughey、Dimitrios Kapogiannis和Barbara S. Slusher等人，在Translational Neurodegeneration期刊上发表最新研究。他们发现，长期给药一种抑制Tau蛋白扩散的小分子口服抑制剂，能够有效减缓阿尔茨海默病（AD）小鼠的Tau蛋白传播，并改善神经炎症等其它AD病理。论文首页截图 中性鞘磷脂酶2（nSMase2）是协助细胞制备细胞外囊泡的关键酶。nSMase2能够将细胞膜中的鞘磷脂裂解成神经酰胺，富集的神经酰胺改变细胞膜物理特性，导致细胞外囊泡出芽。抑制nSMase2的活性，可以改变细胞的囊泡运输机制。 PDDC是由美国约翰霍普金斯大学医学院的研究人员开发的首个具有高度选择性、脑渗透性的nSMase2抑制剂口服药物。在这项研究中，Barbara S. Slusher等人利用Tau病理的AD小鼠模型（P19）探索PDDC的效果。 结果显示，AD小鼠从4个月龄起每周5天口服PDDC（约3mg/天），治疗5个月后，体重变化与常规饲料喂养的AD小鼠相近，没有引起行为异常或肝肾功能的不良影响。 在进行体外实验时，研究者们有个前所未有的发现。他们观察到，转染突变pTau蛋白（人类Tau蛋白）后，大鼠海马神经元的nSMase2活性显著增强，神经酰胺水平明显提高。 与体外实验结果一致，与野生型小鼠相比，AD小鼠的海马神经元nSMase2活性更高、11种神经酰胺水平提高。但是经PDDC治疗的AD小鼠，nSMase2活性和神经酰胺水平的异常升高完全正常化，与野生型小鼠相近。 PDDC治疗对体重和nSMase2活性的影响 进一步研究表明，PDDC治疗不会改善AD小鼠的Tau蛋白过度磷酸化，但可以降低总Tau蛋白水平（P=0.0041）。另外检测到，PDDC能够有效抑制神经元和小胶质细胞产生细胞外囊泡，降低血液和大脑中的细胞外囊泡数量。 研究者们还利用Tau蛋白快速传播的小鼠模型证明，PDDC治疗显著减少Tau蛋白到大脑对侧部分的传播。 PDDC治疗减少Tau蛋白扩散 PDDC的作用不局限于抑制Tau蛋白扩散。AD小鼠实验结果表明，PDDC治疗对保护神经结构和功能具有积极作用，可以减少海马损伤和突触损失。同时，PDDC治疗减少AD小鼠大脑中小胶质细胞和星形胶质细胞的活化，这对于减轻AD的炎症相关病理具有潜在帮助。 总而言之，这项研究首次发现，异常Tau蛋白可以提高海马神经元的nSMase2活性和神经酰胺水平。当异常Tau蛋白表达增加时，nSMase2活性增强、神经酰胺水平升高，促进细胞外囊泡的形成以及异常Tau蛋白的释放和传播，导致更多健康的神经元遭受异常Tau蛋白的迫害。 约翰霍普金斯大学医学院的研究人员开发的口服药物PDDC，可以破解异常Tau蛋白的这一计谋。通过抑制nSMase2活性，PDDC不仅可以直接减少Tau的传播，还可以缓解其它AD病理，比如减少神经炎症和突触损失，使大脑神经酰胺水平正常化。 机制图 在走向临床试验之前，仍需要对PDDC的耐受性进行进一步评估。不过，根据当前的数据， PDDC或可作为一种有前途的治疗新策略，通过减少过度磷酸化Tau的扩散来减缓AD的进展。 参考文献：[1]https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-023-00383-9本文作者丨张艾迪

--Researchers found exposing cells to a small molecule drug improved their fitness during hematopoietic stem cell transplants, which could broaden access and improve outcomes for ex vivo gene therapy– PHILADELPHIA, Sept. 27, 2023 /PRNewswire/ -- A readily available, inexpensive small molecule drug can improve the fitness of hematopoietic stem and progenitor cells (HSPCs) that are modified outside of the body, potentially improving the success of procedures like ex vivo gene therapy, according to a new study by researchers at Children's Hospital of Philadelphia (CHOP). The study, published in the journal Blood, showed that targeting components in the cells called extracellular vesicles (EVs) relieves the stress on cells when outside of the body, improving their performance when they are transplanted back inside. "We initially embarked on this project to better understand the role of these vesicles, assuming – wrongly, as it turns out – that blocking their function would have detrimental effects on the cells," said first author Stephanie Hurwitz, MD, PhD, a research fellow in the Kurre Lab at CHOP and Hematopathologist at the University of Pennsylvania. "We discovered the opposite is true: blocking the formation of these vesicles over a relatively short period of time actually improved the cells' fitness, initiating an adaptive stress response that protects them from the stress of being outside of the body. Ultimately, this serendipitous finding could enhance the quality of transplant products used in treatments like ex vivo gene therapy, improving patient outcomes." Hematopoietic stem cell transplantation (HSCT) involves the transfer of HSPCs from a donor to patients with both benign and malignant diseases. In some cases, as in ex vivo gene therapy, the patient acts as their own donor: the patient's HSPCs are removed, modified outside of the body using gene addition or gene editing, and then transplanted back in. When enough cells are available for modification, this strategy has proven to be a powerful platform for treating genetic blood disorders, including sickle cell disease and beta thalassemia. However, maintaining the fitness of these cells outside of the body poses a challenge, and any loss of fitness introduces the risk that the cells will not properly restore the blood and immune cell system in patients. For this reason, researchers have sought to better understand HSPC programming and signaling so that every attempt could be made to maintain cell health ahead of transplant. One process that we now learn contributes to cell equilibrium is the secretion of EVs, which are important for delivering messages from cell to cell and maintaining proper cell function. However, technical challenges have previously prevented researchers from fully understanding the role these EVs might play in HSPC fitness outside of the body. To explore the role of EVs, the researchers exposed both mouse and human HSPCs to GW4869, a readily available small molecule drug that blocks neutral sphingomyelinase-2 (nSMase2), an enzyme involved in EV formation. The researchers found that an exposure of 24 hours led to sustained improvements in cell fitness and transplantation efficiency after ex vivo culture, with improved rates of blood cell function in mouse models. Additionally, the researchers found that blocking nSMase2 in human CD34+ cells leveled disparities in how well the cells of varying HLA types performed after transplantation into mice. This is of particular interest given important role of HLA in long-term transplantation outcomes. Drilling down on the mechanisms behind these phenomena, the researchers determined that blocking nSMase2 activates an integrated stress response, effectively putting the cells into a state of quiescence, where they are protected from external stressors. This occurs due, in part, from GW4869 disrupting sphingolipid metabolism, which impairs the release of nSMase2-dependent EVs. "While numerous advances have been made over past decades to improve safety and efficiency of HSPC transplantation and ex vivo gene therapy, constraints in cell quantity and graft success continue to limit outcomes," said senior author Peter Kurre, MD, Director of the Pediatric Comprehensive Bone Marrow Failure Center at CHOP. "This important study, which links EV trafficking and the integrated stress response as a regulatory dyad guarding HSPC integrity and long-term fitness, has important implications for potentially broadening patient eligibility to ex vivo gene therapies. Researchers should continue to explore the potential of this small molecule drug in improving ex vivo HSPC culture and transplantation." This research was supported by NIH grants R01-HL164633, 4-R38-HL143613-04 , T32 HL-07439, and P30ES013508. The analyses were made possible through collaboration with the CHOP Flow Cytometry core laboratory, CHOP Department of Veterinary Resources, University of Pennsylvania Stem Cell and Xenograft Core, University of Pennsylvania Hematopoietic Stem Cell Laboratory, CHOP-PENN Proteomics Core Facility, and CHOP Center for Applied Genomics core laboratory. Hurwitz et al. "Neutral sphingomyelinase blockade enhances hematopoietic stem cell fitness through an integrated stress response," Blood, online Sept. 12, 2023, DOI: 10.1182/blood.2023022147 About Children's Hospital of Philadelphia: A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the 595-bed hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as an inpatient hospital with a dedicated pediatric emergency department in King of Prussia. In addition, its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit . Contact: Jennifer Lee Children's Hospital of Philadelphia (267) 426-6084 [email protected] SOURCE Children's Hospital of Philadelphia