Deficient Wnt signalling in synapse degeneration and its contribution to PD

突触变性中 Wnt 信号传导缺陷及其对 PD 的影响

• 批准号: MR/M014045/1
• 负责人: Patricia Salinas
• 金额: $ 79.24万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM014045%2F1
• 关键词: Deficient; Wnt; signalling; synapse; degeneration

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.

在帕金森氏病（PD）中，在称为黑质（SN）的大脑区域中产生多巴胺（DA）的神经细胞或神经元进行性退化。这些神经元与另一个大脑区域纹状体的神经元建立连接，称为突触，纹状体对协调身体运动、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，SN和纹状体之间的连接或突触的丧失有助于在PD患者中观察到的运动缺陷。PD的几种动物模型表现出纹状体中突触的损失和功能障碍，这伴随着在多巴胺神经元死亡不存在或之前的运动协调缺陷。这些发现表明，突触丢失是PD的早期事件。虽然在帕金森病相关基因的鉴定方面取得了很大进展，但对帕金森病中突触的维持机制以及触发突触变性的机制知之甚少。目前没有有效的治愈或治疗方法来减缓或阻止疾病进展。重要的是，在早期阶段检测这种疾病的方法不可用。因此，非常需要了解调节突触稳定性的分子机制以及在PD中触发突触丢失的原因。这些研究将为开发新型治疗靶点提供基础，这些靶点可以保护突触，从而预防或延迟PD的发生。在过去的二十年里，在了解早期发育期间突触如何形成方面取得了巨大进展。然而，人们对成人大脑中神经细胞如何维持连接或突触的了解却少得多。重要的是，目前对神经退行性疾病中触发突触丧失和/或功能障碍的机制知之甚少。我们的研究小组一直在研究的细胞和分子机制，调节突触的形成和生长在年轻的大脑使用小鼠作为模式生物。最近，我们对揭示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丧失。这些小鼠还表现出与在PD动物模型中观察到的那些类似的运动协调缺陷。我们的研究发现了一个分泌蛋白家族在成人大脑突触维持中的新功能。我们的转基因小鼠模型是一个非常宝贵的遗传工具，用于阐明导致成年和衰老大脑突触解体和功能障碍的机制。在这个项目中，我们计划使用这些小鼠来识别蛋白质，有助于突触变性使用新的分子技术。我们将结合分子、细胞、电生理和行为学方法来研究这些分子在纹状体中的功能。这些分子可以作为治疗的目标，旨在保护突触和改善PD的症状。在这个建议中，我们将解决以下问题：1）突触退化的分子基础是什么？2)突触缺失如何影响成年人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受到影响的，这是PD的一个主要风险因素？总的来说，我们的研究将揭示维持和保护纹状体突触的分子机制，从而有助于PD新治疗方法的开发。此外，介导早期突触丢失的分子可以作为早期诊断PD的生物标志物。

项目成果

Wnt signalling tunes neurotransmitter release by directly targeting Synaptotagmin-1.

• DOI: 10.1038/ncomms9302
• 发表时间: 2015-09-24
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Ciani L;Marzo A;Boyle K;Stamatakou E;Lopes DM;Anane D;McLeod F;Rosso SB;Gibb A;Salinas PC
• 通讯作者: Salinas PC

Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling.

• DOI: 10.3389/fnsyn.2021.670467
• 发表时间: 2021
• 期刊: Frontiers in synaptic neuroscience
• 影响因子: 3.7
• 作者: Galli S;Stancheva SH;Dufor T;Gibb AJ;Salinas PC
• 通讯作者: Salinas PC

Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus.

• DOI: 10.1016/j.cub.2016.07.024
• 发表时间: 2016-10-10
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Marzo, Aude;Galli, Soledad;Lopes, Douglas;McLeod, Faye;Podpolny, Marina;Segovia-Roldan, Margarita;Ciani, Lorenza;Purro, Silvia;Cacucci, Francesca;Gibb, Alasdair;Salinas, Patricia C.
• 通讯作者: Salinas, Patricia C.

Evaluation of Synapse Density in Hippocampal Rodent Brain Slices.

• DOI: 10.3791/56153
• 发表时间: 2017-10-06
• 期刊: Journal of visualized experiments : JoVE
• 作者: McLeod F;Marzo A;Podpolny M;Galli S;Salinas P
• 通讯作者: Salinas P