蛋白质组分析显示,在遗传前性痴呆症亚型中,脑脊液的特征是不同的
Aitana Sogorb-Esteve1,2, Sophia Weiner3, Joel Simrén3
1UK Dementia Research Institute at University College London, WC1N 3BG London, UK.
Science translational medicine
|February 5, 2025
概括
这项研究确定了脑脊液 (CSF) 中的蛋白质特征,用于遗传前性痴呆症 (FTD). 在基因形式中发现了明显和共享的蛋白质改变,提供了潜在的诊断生物标志物.
科学领域:
- 神经科学是一个神经科学.
- 蛋白质组学是指蛋白质组学.
- 遗传学 遗传学 是一个
背景情况:
- 前性痴呆症 (FTD) 是一组神经退行性疾病.
- FTD的遗传形式是由C9orf72,GRN和MAPT等基因的突变引起的.
- 了解遗传FTD的分子病理学对于开发诊断和治疗方法至关重要.
研究的目的:
- 在脑脊液 (CSF) 中识别与遗传前性痴呆症 (FTD) 相关的蛋白质特征.
- 调查FTD不同遗传形式 (C9orf72,GRN,MAPT) 中的共享和独特的蛋白质基因变异.
- 确定潜在的蛋白质生物标志物,用于早期检测和基因FTD的预后.
主要方法:
- 在238个脊髓样本上利用了非定向的双重质量标签 (TMT) 蛋白质组学.
- 分析了来自症状前和症状前的突变携带者和突变负对照的样本.
- 采用加权基因共表达网络分析 (WGCNA) 和基因本体学 (GO) 标注.
主要成果:
- 在FTD遗传形式和阿尔茨海默病中确定了共享的蛋白质变异 (例如,神经元素2,脂肪酸结合蛋白3).
- 观察到 lysosomal 蛋白质的差异性变化,MAPT 突变载体的丰度下降.
- 在症状前携带者中检测到与突变相关的蛋白质组变化.
- WGCNA揭示了在神经退行,质反应和突触/溶酶体通路中丰富的蛋白质集群,与疾病严重程度和认知衰退相关.
结论:
- 遗传FTD在CSF中表现出明显的蛋白质变化,为潜在的病理过程提供了洞察力.
- 特定的蛋白质显示出作为遗传FTD的诊断和预后生物标志物候选者的潜力.
- 神经退行,质激活和突触/溶酶体功能障碍是遗传性FTD中的核心生物过程.
相关概念视频
03:03Amyloid Fibrils
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining, normally used to...
01:18Viral Meningitis
Viral meningitis is the most common form of meningitis and is often referred to as aseptic meningitis to indicate the absence of bacterial involvement. It is generally milder than bacterial meningitis, with symptoms including fever, headache, stiff neck, drowsiness, nausea, photophobia, and vomiting. Rarely, more severe manifestations or death may occur. Common causative agents include enteroviruses, particularly coxsackie A and B viruses and echoviruses, all members of the Enterovirus genus...
01:19Cerebral Edema l: Introduction
Cerebral edema is a pathological increase in brain water content that disrupts intracranial pressure regulation and impairs neurological function. Because the cranial vault is rigid, even modest increases in tissue volume can compromise cerebral perfusion, distort neural structures, and initiate secondary injury. Cerebral edema develops through four principal mechanisms: vasogenic, cytotoxic, interstitial, and ionic.Vasogenic EdemaVasogenic edema arises from disruption of the blood–brain...
01:22Cerebral Edema ll: Pathophysiology
Vasogenic edema is a major form of cerebral edema characterized by abnormal accumulation of fluid in the brain’s extracellular space due to disruption of the blood–brain barrier (BBB). The BBB is a specialized structure composed of endothelial cells connected by tight junctions, supported by astrocytic endfeet and a basement membrane. Under normal conditions, it tightly regulates the movement of ions, proteins, and solutes between the bloodstream and brain parenchyma. When this barrier loses...
01:29Alzheimer Disease l: Introduction
Alzheimer disease is a chronic, progressive, and irreversible neurodegenerative disorder and the most common cause of dementia in older adults. It leads to gradual neuronal loss, causing cognitive decline, behavioral changes, and loss of functional independence.Risk Factors and EtiologyThe disease is multifactorial. Age is the strongest risk factor, with prevalence doubling every 5 years after age 65. Genetic factors include mutations in genes such as APP, PSEN1, and PSEN2, which are associated...
01:23Alzheimer Disease ll: Pathophysiology
Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neuritic plaques and intracellular neurofibrillary tangles.Neuritic plaques form in the cerebral cortex and around blood vessels. These plaques contain a dense core of beta-amyloid (Aβ)—a toxic protein fragment that clumps outside neurons. The core is surrounded by damaged neuronal extensions, as well as reactive astrocytes and microglia. Abnormal...