pTDP-43水平与C9orf72ALS/FTD患者前额叶皮层中细胞类型特定的分子变化相关
Hsiao-Lin V Wang1,2, Jian-Feng Xiang1, Chenyang Yuan1,3
1Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322.
概括
C9orf72重复扩张导致ALS/FTD. 这项研究揭示了早期的微质变化和神经元损失,随后是晚期的质变化和RNA变化,揭示了C9orf72-相关的前性痴呆症中的渐进分子缺陷.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
背景情况:
- C9orf72重复扩张是肌缩侧面硬化症和家族前性痴呆症 (ALS/FTD) 的主要遗传原因.
- 了解大脑中的分子病理学对于开发有效治疗方法至关重要.
研究的目的:
- 在C9orf72 ALS/FTD患者的背侧额叶皮质中识别细胞类型特定的分子缺陷.
- 为了将分子变化与疾病进展相关联,使用酸化TARDNA结合蛋白 (pTDP-43) 水平作为生物标志物.
主要方法:
- 对健康对照和C9orf72 ALS/FTD供体脑样本的比较分析.
- 根据pTDP-43水平分期样本,以追踪疾病进展.
- 单细胞分子分析,以确定细胞类型的特定变化.
主要成果:
- 早期的分子事件包括神经监视微质的丧失和补充级联激活,甚至在显著的pTDP-43积累之前.
- 特定的皮层投射神经元 (表达CUX2 / LAMP5) 的减少发生在早期,并随着pTDP-43聚合而恶化.
- 晚期的变化包括质细胞中广泛的染色质变化,早产寡细胞的增加,NEAT1非编码RNA的升高,以及化S6核糖体蛋白的增加.
结论:
- C9orf72 ALS/FTD涉及前额叶皮层中多种细胞类型的渐进性分子和功能变化.
- 微质功能障碍和补体激活在疾病过程的早期出现.
- 这些发现为推动C9orf72相关的神经退行症的复杂机制提供了洞察力.
更多相关视频
11:03Use of Capillary Electrophoresis Immunoassay to Search for Potential Biomarkers of Amyotrophic Lateral Sclerosis in Human Platelets
Published on: February 10, 2020
7.2K
09:36In vivo Positron Emission Tomography to Reveal Activity Patterns Induced by Deep Brain Stimulation in Rats
Published on: March 23, 2022
2.1K
相关概念视频
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...
01:21Huntington Disease l: Introduction
Huntington disease or HD is a progressive, fatal neurodegenerative disorder inherited in an autosomal dominant pattern.PathophysiologyIt is caused by expansion of the CAG trinucleotide repeat in the HTT gene on chromosome 4 (4p16.3), producing an abnormal huntingtin protein with an expanded polyglutamine tract. This misfolded protein disrupts cellular function, leading to neuronal death. Normal alleles have ≤26 repeats, 27–35 are intermediate (risk of expansion), 36–39 show reduced penetrance,...