哈佛沈洁教授最新《Nature》文章

　　

生物通报道，哈佛大学医学院，斯坦福大学分子和细胞生物学系，田纳西州大学的科学家在最新一期的Nature上发表文章Presenilins are essential for regulating neurotransmitter release，解析阿尔茨海默病的最新进展。

 

文章通讯作者是来自哈佛大学医学院的沈洁副教授。沈洁博士用小鼠遗传学方法在老年痴呆症和帕金森综合症的发病机理方面做出了许多重要的贡献。

 

沈洁博士首次证明在成年大脑皮层中引起家族性 AD 的主要基因产物早老素的失活可以导致记忆和突触可塑性受损，并进而引发神经退行病变。该研究为老年痴呆症中功能丧失发病机理提供了证据，还表明突触功能丧失是引起神经退行的发病早期的事件。此外，沈洁博士的实验室首次运用 parkin 缺失小鼠发现了脑黑质网纹体和线粒体功能缺失发生在脑黑质变性之前，说明这些功能丧失可能引发帕金森综合症。最近，沈洁博士的实验室对 DJ-1 基因敲除小鼠的研究表明 DJ-1 在多巴胺能系统以及在 D2 受体介导的功能方面起重要作用。

 

在这篇最新的Nature文章中，沈洁博士主要分析了Presenilins在神经递质释放方面的关键调控作用。Presenilins被认为与家族性阿尔茨海默氏症有关，不过Presenilins究竟在什么方面发挥影响，对神经元有怎样的影响，这些问题一直悬而未决。

 

沈洁研究小组通过建立小鼠模型进行研究，发现Presenilins在突触前腔中发挥作用，控制依赖于活性的神经传输物质的释放，这是一个对于神经计算、学习和记忆来说必不可少的过程。这些发现表明，突触前功能丧失也许是神经退化性疾病中导致痴呆的一个早期原因。

（生物通 小茜）

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Presenilins are essential for regulating neurotransmitter release

 

Chen Zhang1,2, Bei Wu1, Vassilios Beglopoulos1, Mary Wines-Samuelson1, Dawei Zhang1, Ioannis Dragatsis3, Thomas C. Südhof2 & Jie Shen1

Center for Neurologic Diseases, Brigham & Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA

Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, California 94304, USA

Department of Physiology, The University of Tennessee, Health Science Center, Memphis, Tennessee 38163, USA

 

【Abstract】

Mutations in the presenilin genes are the main cause of familial Alzheimer's disease. Loss of presenilin activity and/or accumulation of amyloid- peptides have been proposed to mediate the pathogenesis of Alzheimer's disease by impairing synaptic function1, 2, 3, 4, 5. However, the precise site and nature of the synaptic dysfunction remain unknown. Here we use a genetic approach to inactivate presenilins conditionally in either presynaptic (CA3) or postsynaptic (CA1) neurons of the hippocampal Schaeffer-collateral pathway. We show that long-term potentiation induced by theta-burst stimulation is decreased after presynaptic but not postsynaptic deletion of presenilins. Moreover, we found that presynaptic but not postsynaptic inactivation of presenilins alters short-term plasticity and synaptic facilitation. The probability of evoked glutamate release, measured with the open-channel NMDA (N-methyl-d-aspartate) receptor antagonist MK-801, is reduced by presynaptic inactivation of presenilins. Notably, depletion of endoplasmic reticulum Ca2+ stores by thapsigargin, or blockade of Ca2+ release from these stores by ryanodine receptor inhibitors, mimics and occludes the effects of presynaptic presenilin inactivation. Collectively, these results indicate a selective role for presenilins in the activity-dependent regulation of neurotransmitter release and long-term potentiation induction by modulation of intracellular Ca2+ release in presynaptic terminals, and further suggest that presynaptic dysfunction might be an early pathogenic event leading to dementia and neurodegeneration in Alzheimer's disease.

 

沈洁简介

美国哈佛大学副教授兼上海交通大学“****奖励计划”特聘讲座教授

Jie Shen is Associate Professor of Neurology at Harvard Medical School. She received her Ph.D. in molecular biology from the University of Virginia in 1995 studying mechanisms of alternative splicing in Drosophila. As a postdoctoral fellow with Susumu Tonegawa at MIT, she began the investigation of the molecular basis of Alzheimer’s disease using mouse genetic approaches. Since 1998, she has been directing a molecular neurobiology laboratory at Harvard Medical School whose major research interests focus on the pathogenesis of Alzheimer’s and Parkinson’s diseases. Specifically, the Shen laboratory employs a multidisciplinary approach to investigate the molecular and cellular mechanisms that underlie the pathologic degeneration of specific neuronal populations in the adult central nervous system. Through the generation and analysis of mouse models carrying mutations in disease genes, the Shen laboratory has identified a number of early impairments that may trigger the pathogenic cascade leading to neurodegeneration. For example, recent studies from the Shen laboratory demonstrated that inactivation of presenilins, the major gene products responsible for familial AD, in the adult cerebral cortex results in memory and synaptic plasticity impairments followed by progressive neurodegeneration. The deficits caused by inactivation of presenilins are accompanied by specific molecular changes in the central pathways governing long-term memory, synaptic plasticity and neuronal survival. These findings provide evidence for a loss of function pathogenic mechanism in Alzheimer's disease, and suggest that synaptic dysfunction is the early pathogenic event leading to neuronal degeneration. Similarly, the Shen laboratory has started to investigate systematically in mice the function of genes involved in human Parkinson's disease. Studies of parkin-null mice in the Shen laboratory revealed that nigrostriatal and mitochondrial dysfunction precede nigral degeneration, suggesting that these functional defects may underlie the pathogenesis of parkinsonism. More recently, analysis of DJ-1 knockout mice indicated an essential role of DJ-1 in the dopaminergic system and D2 receptor mediated functions. The Shen laboratory is continuing its investigation of the molecular and cellular mechanisms of neurodegenerative diseases using genomic, proteomic, genetic, biochemical, cell biological, electrophysiological and behavioral approaches.