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

唐氏综合症(DS)患者有三个人类21号染色体(HSA21)副本，而不是正常的两个副本。因此，在DS患者中观察到的症状是由于HSA21基因的过度表达。由于所有患有DS的人在大脑中出现的症状与阿尔茨海默病(AD)相似，因此可能存在一种共同的机制，可以追溯到HSA21的额外基因剂量。我们感兴趣的是其中一个基因，唐氏综合症候选区域1(Dscr1)，它在DS和AD脑中过表达。我们假设Dscr1在调节胞吐作用中起作用，这是一个从细胞中释放化学信使的过程。胞吐作用在大脑中高度专门化，神经递质从神经元突触中释放出来，这一过程被称为突触传递。突触传递减少是DS和AD最早的特征之一，早于DS和AD的经典神经学特征，如斑块形成和痴呆。我们认为Dscr1表达的改变是DS和AD早期观察到的神经元胞吐减少的原因。我们已经产生了Dscr1表达改变的小鼠，就像在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。我们现在希望找到当Dscr1表达改变时，负责调节胞吐作用的细胞内变化。我们还打算将其与具有额外21号染色体的经典DS小鼠模型和具有正常水平的Dscr1的相似DS小鼠模型中的胞吐作用进行比较。本项目将在动物模型中揭示目前未知的Dscr1在胞吐中的功能，使我们能够判断Dscr1是否单独负责改变DS和其他HSA21基因的胞吐，使我们能够更好地了解DS和AD的启动机制，并可能导致对这些疾病进行早期干预的新靶点。

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.