Investigating the relationship between amyloid and synuclein in their effects on synapses and in Alzheimer's and Parkinson's disease.

许多观察表明帕金森病（PD）和阿尔茨海默病（AD）之间以及突触核蛋白（syn）和淀粉样蛋白（A）之间存在某种联系。PD和AD具有共同的神经病理学，因此可能具有共同的病理机制。老年斑是帕金森氏病和其他突触核蛋白病的常见症状。相反，路易体，由syn聚集体组成，其在大多数家族性和散发性AD中存在。最近发现，血液和CSF中的syn和A水平分别是AD和突触核蛋白病的有用生物标志物。PD和AD现在都被认为是synatopathies，并且都在后期阶段以tau病理为特征。事实上，已经发现A和syn的突触效应都是tau依赖性的。syn的片段（称为非淀粉样成分）存在于老年斑中。已经确定突触核蛋白和A肽直接相互作用。据称，-syn是，如果不是一个积极的，至少是一个被动的，在AD的病理生理的球员。最后，寡聚体形式的A增强突触的突触毒性作用的syn和A存款促进播种和传播的syn。我们和其他几个小组已经表明，异常的Wnt信号传导是突触丢失和阿尔茨海默氏症神经病理学其他方面的关键。越来越多的证据表明Wnt调节异常也在帕金森病和其他synuleinopathies中发挥作用。为了支持这一点，Wnt信号传导是多巴胺能神经元分化和存活的关键参与者，并已被建议作为PD治疗干预的途径。PD基因LRRK 2已被证明与Wnt通路的经典和非经典分支的组分相互作用，并在突触内调节两者的活性。第二个PD基因VPS 35也显示出调节Wnt活性。LRRK 2和VPS 35都直接与Wnt受体组分LRP 6相互作用，我们已经证明LRP 6与淀粉样前体蛋白（APP）相互作用，并且是Wnt-ROCK介导的A驱动的突触丢失和神经元A产生的调节剂中的关键参与者。特别地，在进一步支持Wnt-ROCK途径中，ROCK表达在PD小鼠模型中受影响的脑区域中的多巴胺能神经元中改变，并且ROCK抑制保护多巴胺能神经元。本项目的主要目的是揭示突触核蛋白和淀粉样蛋白之间关系的生物化学本质。也就是说，更具体地说，我们的目标是确定这两种蛋白质如何在细胞信号通路中发挥作用，通过这些信号通路，它们各自影响突触功能和形态。该项目的工作假设是，Wnt信号传导是参与这些过程的关键途径，关键目标是确定突触核蛋白在该途径中的位置和作用，该小组已经确定该途径由淀粉样蛋白激活和驱动。

Many observations suggest there is some connection between Parkinson's disease (PD) and Alzheimer's disease (AD) and between synuclein (syn) and amyloid (A). PD and AD have shared neuropathologies and may thus share common pathological mechanisms. Senile plaques, which characterise AD, are frequently present in Parkinson's and other synucleinopathies. Conversely, Lewy bodies, composed of syn aggregates which characterise PD are present in a majority of both familial and sporadic forms of AD. Recently it has been found that levels of syn and A in blood and CSF are, respectively, useful biomarkers for AD and synucleinopathies. PD and AD are both now regarded as synatopathies and both at later stages feature tau pathology. Indeed, the synaptic effects of A and those of syn have both been found to be tau-dependent. A fragment of syn (termed the non-amyloid component) is present in senile plaques. It is well established that the synuclein protein and A peptides directly interact with each other. It is claimed that -syn is, if not an active, is at least a passive, player in the pathophysiology of AD. Finally, oligomeric forms of A enhance the synaptotoxic effects of syn and A deposits promote the seeding and spread of syn. We, and several other groups, have shown that aberrant Wnt signalling is key to synapse loss and other aspects of Alzheimer's neuropathology. Growing evidence indicates a dysregulation of Wnt also plays a role in Parkinson's and other synuleinopathies. In support of this Wnt signaling is a key player in dopaminergic neuronal differentiation and survival and has been suggested as an avenue for therapeutic intervention for PD. The PD gene LRRK2 has been shown to interact with components of the canonical and non-canonical branches of Wnt pathways and to modulate the activity of both, within the synapse. A second PD gene, VPS35, has also been shown to modulate Wnt activity. Both LRRK2 and VPS35 directly interact with the Wnt receptor component, LRP6, which we have shown interacts with the amyloid precursor protein (APP) and is a crucial player in Wnt-ROCK-mediated, A-driven synapse loss and a modulator of neuronal A production. In further support of the Wnt-ROCK pathway in particular, ROCK expression is altered in dopaminergic neurons in affected brain regions in mouse models of PD and ROCK inhibition protects dopaminergic neurons. The major aim of this project is to uncover the biochemical nature of the relationship between synuclein and amyloid. That is, more specifically we aim to determine how the two proteins act in the cell signalling pathway through which they each impact synapse function and morphology. It is the working hypothesis of the project that Wnt signalling is key pathway involved in these processes and the key aim is to determine where and what role synuclein plays in this pathway, which the group have already established is activated and driven by amyloid.