Complement-Microglia Interaction in Synaptic Loss and Neurodegeneration in HD

描述（由申请人提供）：（HD）是最常见的常染色体显性神经退行性疾病（NDD），其特征是不自主运动、认知和精神症状以及持续的疾病进展。HD是由突变的亨廷顿蛋白（mHTT）基因的CAG重复扩增引起的；然而，HD发病机制的分子机制尚不清楚。目前，迫切需要验证新的治疗靶点来预防或改变HD的发病机制。越来越多的证据表明，年龄依赖性ndd（包括HD）的一个标志是早期神经元功能障碍和中枢神经系统突触丧失，随后是进行性神经退行性变。最近的研究支持了补体系统在发育和疾病期间突触修剪中意想不到的作用。在青光眼小鼠模型的发育过程中，补体蛋白C1q和C3定位于突触并介导突触消除。我们最近的研究支持一种模型，即发育中的大脑中“较弱”或较不活跃的突触被补体“标记”，然后被小胶质细胞（CNS中表达吞噬补体受体（即CR3/Cd11b）的初级吞噬免疫细胞）消除。我们认为类似的补体和小胶质细胞依赖机制有助于突触丢失，这反过来对HD的行为缺陷和选择性神经退行性变的发病机制至关重要。在人类HD脑组织和几种HD小鼠模型中已经观察到补体上调和小胶质细胞激活，我们大量的新数据显示，补体因子（C1q和C3）上调并标记在全长mHTT HD小鼠模型（BACHD）中已知突触丢失的易感脑区（即纹状体）的突触。Yang实验室最近的研究表明，BACHD小鼠的行为缺陷、选择性脑萎缩和纹状体突触毒性依赖于皮质-纹状体神经元的相互作用。基于这些强有力的初步数据，我们假设补体系统通过补体和小胶质细胞介导的突触丧失（HD小鼠皮质纹状体神经元活性降低）参与HD发病的早期阶段。为了验证这一假设，我们将研究Yang实验室开发的一种创新条件HD小鼠模型，以确定补体是否针对皮质纹状体回路进行消除，以及光遗传学恢复神经元活动或遗传减少/治疗性抗体抑制补体级联（C3和C1q）是否可以改善HD小鼠的突触丧失、神经变性和行为障碍。我们的研究可以验证补体级联（如C3）及其与小胶质细胞的相互作用是HD发病的关键机制，并为HD治疗中抑制该途径提供支持。

DESCRIPTION (provided by applicant): (HD) is the most common autosomal dominant neurodegenerative disorder (NDD), and is characterized by involuntary movement, cognitive and psychiatric symptoms, and relentless disease progression. HD is caused by a CAG repeat expansion in the mutant Huntingtin (mHTT) gene; however the molecular mechanisms underlying HD pathogenesis remain poorly understood. Currently, there is an urgent need to validate novel therapeutic targets to prevent or modify HD pathogenesis. Growing evidence suggests that a hallmark of age-dependent NDDs, including HD, is early neuronal dysfunction and loss of CNS synapses, followed by progressive neurodegeneration. Recent research supports an unexpected role of the complement system in synaptic pruning during development and disease. During development, and in a mouse model of glaucoma, complement proteins C1q and C3 localize to synapses and mediate synapse elimination. Our recent studies support a model in which "weaker" or less active synapses in the developing brain are "tagged" by complement and then eliminated by microglia, the primary phagocytic immune cells in CNS that express phagocytic complement receptors (i.e. CR3/Cd11b). We propose that similar complement and microglia-dependent mechanisms contribute to synapse loss, which in turn is crucial to pathogenesis of behavioral deficits and selective neurodegeneration in HD. Complement upregulation and microglial activation have been observed in human HD brain tissue and several HD mouse models, and our substantial new data showed complement factors (C1q and C3) are upregulated and tagged the synapses in the vulnerable brain regions (i.e. striatum) with known synapse loss in a full-length mHTT HD mouse model (BACHD). Recent study from Yang lab showed that behavioral deficits, selective brain atrophy and striatal synaptic toxicities in BACHD mice dependent on interaction between cortico-striatal neuronal interactions. Based on these strong preliminary data, we hypothesize that the complement system contributes to early stages of HD pathogenesis through complement- and microglia-mediated synaptic loss as a result of reduced cortico-striatal neuronal activity in HD mice. To test this hypothesis, we will study an innovative conditional HD mouse model developed by the Yang lab to determine whether complement targets cortico-striatal circuits for elimination, and whether optogenetic restoration of neuronal activities or genetic reduction/therapeutic antibody-based inhibition of the complement cascade (C3 and C1q) could ameliorate synapse loss, neurodegeneration, and behavioral impairments in HD mice. Our study could validate complement cascade (e.g. C3) and its interactions with microglia as a critical mechanism in HD pathogenesis, and provide support on the inhibition of this pathway in HD therapy.