U. Wormser, A. Sintov, M. Vinceti, J. Mandrioli, B. Brodsky, E. Proscura, Y. Finkelstein
{"title":"独特的脑脊液肽:潜在的肌萎缩侧索硬化症生物标志物和致病因素","authors":"U. Wormser, A. Sintov, M. Vinceti, J. Mandrioli, B. Brodsky, E. Proscura, Y. Finkelstein","doi":"10.37349/ent.2023.00060","DOIUrl":null,"url":null,"abstract":"Aim: Amyotrophic lateral sclerosis (ALS) is a progressive disease of unknown etiology, characterized by degeneration of motoneurons and skeletal muscle strength decline that progressively evolves to respiratory failure and death. A key point in the therapeutic approach is to understand the pathological processes associated with disease evolution. In spite of intensive research on the molecular/cellular mechanisms involved in ALS initiation and progression disease etiology, unfortunately, poorly understood and there is no efficient specific/decisive treatment for ALS patients. The aims of the present study are to identify specific factors in the cerebrospinal fluid (CSF) of ALS patients and to test their potential relevance to the etiology of this disease. Methods: Peptides were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Motor activity of mice was tested by the Rota-rod test and peptide-induced inflammation was assessed by induction nitric oxide synthase activity in BV2 microglia cells. Results: Analysis of CSF samples of ALS patients (n = 15) detected two peptides, C-terminal fragments of transthyretin and osteopontin, which were absent in a control group (n = 15). In addition to being potential biomarker candidates, the relevancy of these peptides to the disease etiology was tested by assessing their effects on motor activity in mice and inflammation model in cell culture. Intranasal administration of the peptides reduced motor activity in the Rota-rod test and activated lipopolysaccharide-induced inflammation in BV2 microglia cells. Conclusions: These findings suggest that during ALS onset and progression two potentially neurotoxic peptides are formed, released, or penetrated the central nervous system thus inducing neuroinflammation and neurodegeneration.","PeriodicalId":73000,"journal":{"name":"Exploration of neuroprotective therapy","volume":"30 S1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Unique cerebrospinal fluid peptides: potential amyotrophic lateral sclerosis biomarkers and etiological factors\",\"authors\":\"U. Wormser, A. Sintov, M. Vinceti, J. Mandrioli, B. Brodsky, E. Proscura, Y. Finkelstein\",\"doi\":\"10.37349/ent.2023.00060\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Aim: Amyotrophic lateral sclerosis (ALS) is a progressive disease of unknown etiology, characterized by degeneration of motoneurons and skeletal muscle strength decline that progressively evolves to respiratory failure and death. A key point in the therapeutic approach is to understand the pathological processes associated with disease evolution. In spite of intensive research on the molecular/cellular mechanisms involved in ALS initiation and progression disease etiology, unfortunately, poorly understood and there is no efficient specific/decisive treatment for ALS patients. The aims of the present study are to identify specific factors in the cerebrospinal fluid (CSF) of ALS patients and to test their potential relevance to the etiology of this disease. Methods: Peptides were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Motor activity of mice was tested by the Rota-rod test and peptide-induced inflammation was assessed by induction nitric oxide synthase activity in BV2 microglia cells. Results: Analysis of CSF samples of ALS patients (n = 15) detected two peptides, C-terminal fragments of transthyretin and osteopontin, which were absent in a control group (n = 15). In addition to being potential biomarker candidates, the relevancy of these peptides to the disease etiology was tested by assessing their effects on motor activity in mice and inflammation model in cell culture. Intranasal administration of the peptides reduced motor activity in the Rota-rod test and activated lipopolysaccharide-induced inflammation in BV2 microglia cells. Conclusions: These findings suggest that during ALS onset and progression two potentially neurotoxic peptides are formed, released, or penetrated the central nervous system thus inducing neuroinflammation and neurodegeneration.\",\"PeriodicalId\":73000,\"journal\":{\"name\":\"Exploration of neuroprotective therapy\",\"volume\":\"30 S1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-12-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Exploration of neuroprotective therapy\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.37349/ent.2023.00060\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Exploration of neuroprotective therapy","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.37349/ent.2023.00060","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
目的:肌萎缩性脊髓侧索硬化症(ALS)是一种病因不明的渐进性疾病,以运动神经元变性和骨骼肌力量下降为特征,并逐渐演变为呼吸衰竭和死亡。治疗方法的一个关键点是了解与疾病演变相关的病理过程。遗憾的是,尽管对参与肌萎缩性脊髓侧索硬化症发病和进展的分子/细胞机制进行了深入研究,但人们对该病的病因却知之甚少,也没有针对肌萎缩性脊髓侧索硬化症患者的有效的特异性/决定性治疗方法。本研究旨在确定 ALS 患者脑脊液(CSF)中的特定因子,并检测其与该疾病病因的潜在相关性。研究方法采用液相色谱串联质谱法(LC-MS/MS)鉴定肽类物质。通过罗塔杆试验测试小鼠的运动能力,并通过诱导 BV2 小胶质细胞中一氧化氮合酶的活性来评估肽诱导的炎症。结果对 ALS 患者(15 人)的脑脊液样本进行分析,发现了两种肽,即转甲状腺素和骨化素的 C 端片段,对照组(15 人)中没有发现这两种肽。这些肽除了是潜在的候选生物标记物外,还通过评估它们对小鼠运动活动和细胞培养炎症模型的影响,检验了它们与疾病病因的相关性。鼻内给药可降低小鼠在罗塔杆试验中的运动活性,并激活脂多糖诱导的 BV2 小胶质细胞炎症。结论:这些研究结果表明,在渐冻症发病和发展过程中,有两种潜在的神经毒性肽形成、释放或渗透到中枢神经系统,从而诱发神经炎症和神经变性。
Aim: Amyotrophic lateral sclerosis (ALS) is a progressive disease of unknown etiology, characterized by degeneration of motoneurons and skeletal muscle strength decline that progressively evolves to respiratory failure and death. A key point in the therapeutic approach is to understand the pathological processes associated with disease evolution. In spite of intensive research on the molecular/cellular mechanisms involved in ALS initiation and progression disease etiology, unfortunately, poorly understood and there is no efficient specific/decisive treatment for ALS patients. The aims of the present study are to identify specific factors in the cerebrospinal fluid (CSF) of ALS patients and to test their potential relevance to the etiology of this disease. Methods: Peptides were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Motor activity of mice was tested by the Rota-rod test and peptide-induced inflammation was assessed by induction nitric oxide synthase activity in BV2 microglia cells. Results: Analysis of CSF samples of ALS patients (n = 15) detected two peptides, C-terminal fragments of transthyretin and osteopontin, which were absent in a control group (n = 15). In addition to being potential biomarker candidates, the relevancy of these peptides to the disease etiology was tested by assessing their effects on motor activity in mice and inflammation model in cell culture. Intranasal administration of the peptides reduced motor activity in the Rota-rod test and activated lipopolysaccharide-induced inflammation in BV2 microglia cells. Conclusions: These findings suggest that during ALS onset and progression two potentially neurotoxic peptides are formed, released, or penetrated the central nervous system thus inducing neuroinflammation and neurodegeneration.