Early mechanisms of pathobiology are revealed by transcriptional temporal dynamics in hippocampal CA1 neurons of prion infected mice.
Early mechanisms of pathobiology are revealed by transcriptional temporal dynamics in hippocampal CA1 neurons of prion infected mice.
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DOI：
10.1371/journal.ppat.1003002
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Booth SA
中科院分区：
文献类型：
--
作者：
Majer A;Medina SJ;Niu Y;Abrenica B;Manguiat KJ;Frost KL;Philipson CS;Sorensen DL;Booth SA
朊病毒疾病通常有很长的临床前潜伏期，在此期间，传染性朊病毒颗粒和传染性在大脑中稳定传播。异常神经炎发芽和突触缺陷在临床前疾病期间是明显的，然而，直到临床阶段开始才检测到大体神经元损失。伴随早期神经元损伤并最终导致神经元死亡的分子事件仍然不清楚。在这项研究中，我们使用激光捕获显微切割分离海马CA 1神经元，并确定其在感染过程中的临床前转录反应。我们发现，这些神经元内的基因表达是动态的，其特征在于活动的不同阶段。我们发现，一个主要的基因簇在临床前疾病期间发生改变，之后表达要么恢复到基础水平，要么在临床疾病期间发生直接逆转。引人注目的是，我们发现，这个集群包含一个签名高度联想到突触N-甲基-D-天冬氨酸（NMDA）受体信号和神经保护通路的激活。此外，参与神经元投射和树突发育的基因在整个疾病过程中也发生了改变，最终导致突触蛋白基因表达的普遍下降。类似地，去调控的miRNA如miR-132- 3 p、miR-124 a-3 p、miR-16- 5 p、miR-26 a-5 p、miR-29 a-3 p和miR-140- 5 p遵循伴随的表达模式。这是第一个深入的基因组研究，描述了海马神经元对早期朊病毒复制的临床前反应。我们的研究结果表明，朊病毒复制的结果在一个程序化的反应，介导的持续刺激，至少部分，突触NMDA受体的活性，最初促进细胞存活和轴突重塑。然而，这种反应在受感染的海马体出现临床症状之前就终止了，这似乎表明了疾病的关键时刻。这些早期神经保护通路的操作可能会纠正退化和生存之间的平衡，为治疗提供了一个潜在的进展。神经退行性疾病影响越来越多的人口;因此，迫切需要开发治疗方法。朊病毒疾病属于这组疾病，虽然罕见且具有独特的传播性，但在亚细胞水平上具有许多共同特征。疾病的核心是渐进性突触损伤，其总是导致神经元的不可逆损失。理解这一过程无疑对合理的药物发现至关重要。在这项研究中，我们观察了疾病早期的神经元，当时朊病毒几乎无法检测到，也没有观察到临床症状。具体来说，我们进行了一个全面的分析，在一个特别密集的区域内的神经元，CA 1海马区，从朊病毒感染和对照小鼠的转录变化。通过这种方式，我们能够丰富神经元特有的分子变化的数据，并最大限度地减少支持细胞（如星形胶质细胞和小胶质细胞）的变化。我们检测到一个转录程序的激活，表明这些神经元在疾病早期的保护机制。这种机制随着疾病的进展而减弱，并随着临床症状的出现而完全消失。这些发现证明了神经元对朊病毒的初始神经保护反应的能力，这可以用于治疗开发。
Prion diseases typically have long pre-clinical incubation periods during which time the infectious prion particle and infectivity steadily propagate in the brain. Abnormal neuritic sprouting and synaptic deficits are apparent during pre-clinical disease, however, gross neuronal loss is not detected until the onset of the clinical phase. The molecular events that accompany early neuronal damage and ultimately conclude with neuronal death remain obscure. In this study, we used laser capture microdissection to isolate hippocampal CA1 neurons and determined their pre-clinical transcriptional response during infection. We found that gene expression within these neurons is dynamic and characterized by distinct phases of activity. We found that a major cluster of genes is altered during pre-clinical disease after which expression either returns to basal levels, or alternatively undergoes a direct reversal during clinical disease. Strikingly, we show that this cluster contains a signature highly reminiscent of synaptic N-methyl-D-aspartic acid (NMDA) receptor signaling and the activation of neuroprotective pathways. Additionally, genes involved in neuronal projection and dendrite development were also altered throughout the disease, culminating in a general decline of gene expression for synaptic proteins. Similarly, deregulated miRNAs such as miR-132-3p, miR-124a-3p, miR-16-5p, miR-26a-5p, miR-29a-3p and miR-140-5p follow concomitant patterns of expression. This is the first in depth genomic study describing the pre-clinical response of hippocampal neurons to early prion replication. Our findings suggest that prion replication results in the persistent stimulation of a programmed response that is mediated, at least in part, by synaptic NMDA receptor activity that initially promotes cell survival and neurite remodelling. However, this response is terminated prior to the onset of clinical symptoms in the infected hippocampus, seemingly pointing to a critical juncture in the disease. Manipulation of these early neuroprotective pathways may redress the balance between degeneration and survival, providing a potential inroad for treatment. Neurodegenerative diseases affect an ever-increasing proportion of the population; therefore, there is an urgent need to develop treatments. Prion disorders belong to this group of diseases and although rare and uniquely transmissible, share many features on a sub-cellular level. Central to disease is progressive synaptic impairment that invariably leads to the irreversible loss of neurons. Understanding this process is undoubtedly essential for rational drug discovery. In this study we looked at neurons very early in disease, when prions are barely detectable and there are no clinical symptoms observed. Specifically, we performed a comprehensive analysis of transcriptional changes within a particularly dense area of neurons, the CA1 hippocampus region, from prion-infected and control mice. In this way we were able to enrich our data for molecular changes unique to neurons and minimize those changes characteristic of support cells such as astrocytes and microglia. We detected the activation of a transcriptional program indicative of a protective mechanism within these neurons early in disease. This mechanism diminished as disease progressed and was lost altogether, concurrently with the onset of clinical symptoms. These findings demonstrate the ability of neurons to mount an initial neuroprotective response to prions that could be exploited for therapy development.
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DOI：
10.1046/j.1365-2990.2000.026002143.x
发表时间：
2000-04-01
影响因子：
5
作者：
Belichenko, PV;Brown, D;Fraser, JR
通讯作者：
Fraser, JR
影响因子：
3.5
作者：
Ango, F;Robbe, D;Fagni, L
通讯作者：
Fagni, L
影响因子：
--
作者：
Antoni, FA;Sosunov, AA;Simpson, J
通讯作者：
Simpson, J
DOI：
10.1073/pnas.93.23.13148
发表时间：
1996-11-12
影响因子：
11.1
作者：
Brandner, S;Raeber, A;Aguzzi, A
通讯作者：
Aguzzi, A
DOI：
10.1523/jneurosci.3109-08.2008
发表时间：
2008-12-03
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chiesa R;Piccardo P;Biasini E;Ghetti B;Harris DA
通讯作者：
Harris DA