Deficient Wnt signalling in synapse degeneration and its contribution to PD

在帕金森氏病(PD)中，大脑黑质(SN)区域中产生多巴胺(DA)的神经细胞或神经元逐渐退化。这些神经元与大脑的另一个区域纹状体中的神经元建立联系，称为突触，纹状体对于协调身体运动、调节精细运动(称为灵巧性)和抑制不自主运动至关重要。因此，黑质和纹状体之间的连接或突触的丢失会导致帕金森病患者的运动障碍。几种帕金森病动物模型显示纹状体突触丢失和功能障碍，在多巴胺神经元死亡之前或缺失时伴有运动协调缺陷。这些发现表明，突触丢失是帕金森病的早期事件。尽管一些参与帕金森病的基因的鉴定已经取得了很大的进展，但对帕金森病中突触维持的机制以及是什么触发了突触变性，人们知之甚少。目前还没有有效的治疗方法或治疗方法来减缓或阻止帕金森病的进展。重要的是，在早期阶段检测这种疾病的方法是不可用的。因此，有必要了解调控突触稳定性的分子机制，以及是什么触发了它们在帕金森病中的丢失。这些研究将为开发新的治疗靶点以保护突触从而预防或延缓PDs的发生提供基础。在过去的二十年里，在理解突触在早期发育过程中如何形成方面取得了很大的进展。然而，关于神经细胞如何在成人大脑中维持它们的连接或突触的了解要少得多。重要的是，人们对神经退行性疾病中触发突触丢失和/或功能障碍的机制知之甚少。我们的研究小组一直在以小鼠为模式生物，研究调节年轻大脑中突触形成和生长的细胞和分子机制。最近，我们开始对揭开神经退行性疾病中触发突触丢失的机制感兴趣。为了研究突触变性，我们建立了一个转基因小鼠模型，该模型在大脑中产生一种分泌蛋白，导致成年纹状体中突触的丢失。这些小鼠也表现出与帕金森病动物模型中观察到的运动协调缺陷类似的缺陷。我们的研究发现了一个分泌蛋白家族在成人大脑中维持突触的新功能。我们的转基因小鼠模型是一个宝贵的遗传工具，可以用来阐明导致成年和衰老大脑中突触分解和功能障碍的机制。在这个项目中，我们计划使用这些小鼠来利用新的分子技术来识别导致突触退化的蛋白质。我们将结合分子、细胞、电生理和行为学的方法来描述这些分子在纹状体中的功能。这些分子可以作为治疗靶点，旨在保护突触和改善帕金森病的症状。在这个提案中，我们将解决以下问题：1)突触变性的分子基础是什么？2)突触丢失如何影响成年纹状体内的神经元回路？3)突触脆弱性在衰老过程中是如何影响的，突触易损性是帕金森病的主要危险因素？总体而言，我们的研究将为维持和保护纹状体突触的分子机制提供新的线索，从而有助于开发治疗帕金森病的新方法。此外，介导早期突触丢失的分子可以作为早期诊断帕金森病的生物标志物。

In Parkinson's disease (PD), dopamine (DA) producing nerve cells or neurons in a brain area called substantia nigra (SN) progressively degenerate. These neurons make connections, called synapses, with neurons in another brain area, the striatum, which is essential for coordination of body movement, regulation of fine-motor movement (known as dexterity) and inhibition of involuntary movement. Thus, the loss of connections or synapses between the SN and the striatum contributes to motor deficits observed in people with PD. Several animal models of PD exhibit loss and dysfunction of synapses in the striatum, which is accompanied by defects in motor coordination in the absence or before dopamine neuron death. These findings suggest that synapse loss is an early event in PD. Although great progress has been made in the identification of some of genes involved in PD, little is known about the mechanisms that contribute to the maintenance of synapses and what triggers synapse degeneration in PD. Currently no effective cure or treatments to slow or stop disease progression are available for PD. Importantly, methods for detection of this disease at early stages are not available. Therefore, there is a great need to understand the molecular mechanisms that regulate synapse stability and what triggers their loss in PD. These studies will provide the foundations for the development of novel therapeutic targets that protect synapses and therefore prevent or delay the onset of PDIn the last two decades, great progress has been made in understanding how synapses form during early development. However, much less is known about how nerve cells maintain their connections or synapses in the adult brain. Importantly, there is very little knowledge of the mechanisms that trigger the loss and/or dysfunction of synapses in neurodegenerative diseases. Our research group has been studying the cellular and molecular mechanisms that regulate the formation and growth of synapses in the young brain using the mouse as a model organism. Recently, we have become interested in unraveling the mechanisms that triggers synapse loss in neurodegenerative diseases. With the aim to study synapse degeneration, we generated a transgenic mouse model that produces a secreted protein in the brain resulting in the loss of synapses in the adult striatum. These mice also exhibit defects in motor coordination similar to those observed in animal models of PD. Our studies led to the discovery of a novel function for a family of secreted proteins in synapse maintenance in the adult brain. Our transgenic mouse model is an invaluable genetic tool for elucidating the mechanisms that lead to synapse disassembly and dysfunction in the adult and ageing brain. In this project, we plan to use these mice to identify the proteins that contribute to synapse degeneration using novel molecular techniques. We will characterise the function of these molecules in the striatum using a combination of molecular, cellular, electrophysiological and behavioural approaches. These molecules could serve as therapeutic targets aimed at protecting synapses and ameliorating the symptoms in PD. In this proposal we will address the following questions: 1) What are the molecular underpinnings of synapse degeneration? 2) How does synapse loss affect neuronal circuits within the adult striatum? 3) How is synapse vulnerability affected during aging, a major risk factor for PD? Overall our studies will shed new light into the molecular mechanisms that maintain and protect synapses in the striatum and therefore contribute to the development of new treatments for PD. Moreover, molecules that mediate early synaptic loss could serve as biomarkers to diagnose PD at early stages.