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REGULATION OF ER-MITOCHONDRIA CONTACTS IN NEURODEGENERATION

神经变性中线粒体接触的调节

基本信息

批准号：
MR/S025979/1
负责人：
Kurt De Vos
金额：
$ 79.3万
依托单位：
University of Sheffield
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS025979%2F1
关键词：
REGULATION ER MITOCHONDRIA CONTACTS NEURODEGENERATION

项目摘要

In the brain, approximately 100 billion nerve cells allow us to think, remember, see, hear, speak etc. Inside of the nerve cells there are different compartments, called organelles. We call them organelles because for a cell they are more or less what an organ such as the liver is for the whole body. Organelles are surrounded by membranes; you can compare them to little balloons. Just as organs, organelles have specific functions. We are particularly interested in two of these organelles, called mitochondria and ER (ER is short for Endoplasmic Reticulum). Mitochondria are the organelles that convert the food we eat into a form of energy that the cells can use. They basically are the power stations of the body. The ER is the place in the cell where various building blocks of the cell, called proteins and lipids are made and then sent to specific places in the cell. Mitochondria and ER can swap energy and building blocks between them at places where the organelles touch. We call these places contact sites. It has become clear that when contact sites between ER and mitochondria are disrupted that this contributes to brain diseases such as motor neuron disease, dementia and Parkinson's disease. We don't know why this is so.We have discovered a new mechanism that controls the amount of contact there is between the ER and mitochondria, and we believe that overactivation of this mechanism might be the reason that there is loss of contact in disease.The purpose of this project is to investigate this new mechanism so that we can better understand what is going on. Once we know this we will try to use this knowledge to find new ways of restoring the contacts between the organelles. Once we can restore the contacts we can answer the question if this protects neurones in a dish from dying. Our hope is that this will be the case and that we can use what we learn in this project as the starting point to develop new drugs to treat brain diseases.

在大脑中，大约有1000亿个神经细胞让我们思考，记忆，看，听，说话等，神经细胞内部有不同的隔间，称为细胞器。我们称它们为细胞器，因为它们对于细胞来说或多或少就像肝脏这样的器官对于整个身体一样。细胞器被膜包围;你可以把它们比作小气球。就像器官一样，细胞器有特定的功能。我们对其中两种细胞器特别感兴趣，称为线粒体和ER（ER是内质网的缩写）。线粒体是一种细胞器，它将我们吃下的食物转化为细胞可以使用的能量形式。它们基本上是身体的发电站。ER是细胞中的一个地方，在那里制造了细胞的各种构建模块，称为蛋白质和脂质，然后将其发送到细胞中的特定位置。线粒体和内质网可以在细胞器接触的地方交换能量和积木。我们称这些地方为接触点。很明显，当ER和线粒体之间的接触部位被破坏时，这会导致大脑疾病，如运动神经元疾病，痴呆症和帕金森病。我们不知道为什么会这样。我们发现了一种新的机制来控制ER和线粒体之间的接触量，我们相信这种机制的过度激活可能是疾病中失去联系的原因。这个项目的目的是调查这种新机制，以便我们能够更好地了解发生了什么。一旦我们知道了这一点，我们将尝试使用这些知识，找到新的方法来恢复细胞器之间的联系。一旦我们能够恢复接触，我们就可以回答这个问题，如果这可以保护培养皿中的神经元免于死亡。我们的希望是，这将是事实，我们可以使用我们在这个项目中所了解的作为起点，开发新的药物来治疗脑部疾病。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation.

DOI：
10.3389/fncel.2022.1061559
发表时间：
2022
期刊：
FRONTIERS IN CELLULAR NEUROSCIENCE
影响因子：
5.3
作者：
Bauer, Claudia S.;Webster, Christopher P.;Shaw, Allan C.;Kok, Jannigje R.;Castelli, Lydia M.;Lin, Ya-Hui;Smith, Emma F.;Illanes-Alvarez, Francisco;Higginbottom, Adrian;Shaw, Pamela J.;Azzouz, Mimoun;Ferraiuolo, Laura;Hautbergue, Guillaume M.;Grierson, Andrew J.;De Vos, Kurt J.
通讯作者：
De Vos, Kurt J.

An interaction between synapsin and C9orf72 regulates excitatory synapses and is impaired in ALS/FTD.

突触蛋白和 C9orf72 之间的相互作用调节兴奋性突触，并在 ALS/FTD 中受损。

DOI：
10.1007/s00401-022-02470-z
发表时间：
2022-09
期刊：
Acta neuropathologica
影响因子：
12.7
作者：
通讯作者：

C9ORF72-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons.

DOI：
10.26508/lsa.202101276
发表时间：
2022-09
期刊：
LIFE SCIENCE ALLIANCE
影响因子：
4.4
作者：
Marchi, Paolo M.;Marrone, Lara;Brasseur, Laurent;Coens, Audrey;Webster, Christopher P.;Bousset, Luc;Destro, Marco;Smith, Emma F.;Walther, Christa G.;Alfred, Victor;Marroccella, Raffaele;Graves, Emily J.;Robinson, Darren;Shaw, Allan C.;Wan, Lai Mei;Grierson, Andrew J.;Ebbens, Stephen J.;De Vos, Kurt J.;Hautbergue, Guillaume M.;Ferraiuolo, Laura;Melki, Ronald;Azzouz, Mimoun
通讯作者：
Azzouz, Mimoun