The role of Down syndrome candidate region 1 (DSCR1) in neurotransmitter release, vesicle recycling and Down syndrome.

唐氏综合症候选区域 1 (DSCR1) 在神经递质释放、囊泡回收和唐氏综合症中的作用。

• 批准号: nhmrc : 441112
• 负责人: Prof Damien Keating
• 金额: $ 23.49万
• 依托单位: Flinders University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/role-syndrome-candidate-recycling-syndrome/80938
• 关键词: role; Down; syndrome; candidate; region

Individuals with Down syndrome (DS) have three copies of human chromosome 21 (HSA21), rather than the normal two. The symptoms observed in DS individuals are therefore due to the overexpression of HSA21 genes. Since all individuals with DS develop symptoms in the brain similar to those see in Alzheimer's disease (AD), there may be a common mechanism that can be traced to the extra gene dosage from HSA21. We are interested in one of these genes, Down syndrome candidate region 1 (Dscr1), which is overexpressed in both DS and AD brains. We hypothesise that Dscr1 has a role in regulating exocytosis, a process in which chemical messengers are released from cells. Exocytosis is highly specialised in the brain where neurotransmitters are released from neuronal synapses in a process known as synaptic transmission. Reduced synaptic transmission is one of the earliest hallmark of DS and AD occurring long before the classical neurological traits of DS and AD such as plaque formation and dementia. We propose that alterations in Dscr1 expression are responsible for the reduced neuronal exocytosis observed in the early stages of DS and AD. We have generated mice in which Dscr1 expression is altered, as occurs in DS and AD brains, and our preliminary studies indicate that exocytosis is reduced in these mice. We now wish to find the intracellular changes responsible for regulating exocytosis when Dscr1 expression is altered. We also aim to compare this to exocytosis in classical DS mouse models which have an extra chromosome 21 and in similar DS mouse models which have normal levels of Dscr1. This project will uncover the currently unknown functions of Dscr1 in exocytosis in an animal model, allow us to gauge whether Dscr1 is solely responsible for altering exocytosis in DS amongst other HSA21 genes, enable us to better understand the mechanisms initiating DS and AD and possibly lead to new targets of early intervention in these diseases.

唐氏综合征（DS）患者有三个人类21号染色体（HSA 21）拷贝，而不是正常的两个。因此，在DS个体中观察到的症状是由于HSA 21基因的过表达。由于所有患有DS的个体在大脑中都会出现类似于阿尔茨海默病（AD）的症状，因此可能存在一种共同的机制，可以追溯到HSA 21的额外基因剂量。我们感兴趣的是其中一个基因，唐氏综合征候选区域1（DRD1），它在DS和AD大脑中过表达。我们假设DAP1在调节胞吐作用中起作用，这是一个化学信使从细胞中释放的过程。胞吐作用在大脑中高度专门化，其中神经递质在称为突触传递的过程中从神经元突触释放。突触传递减少是DS和AD的最早标志之一，早在DS和AD的经典神经学特征如斑块形成和痴呆之前就发生了。我们认为，DSP1表达的改变是导致DS和AD早期神经元胞吐减少的原因。我们已经产生了DSP1表达改变的小鼠，如在DS和AD脑中发生的那样，我们的初步研究表明，这些小鼠的胞吐作用减少。我们现在希望找到细胞内的变化，负责调节胞吐作用时，DAP1的表达被改变。我们还旨在将其与具有额外21号染色体的经典DS小鼠模型和具有正常水平DSP1的类似DS小鼠模型中的胞吐进行比较。该项目将在动物模型中揭示目前未知的DAD1在胞吐中的功能，使我们能够衡量DAD1是否仅负责改变DS中的胞吐以及其他HSA 21基因，使我们能够更好地了解引发DS和AD的机制，并可能导致这些疾病早期干预的新靶点。