Complement-Microglia Interaction in Synaptic Loss and Neurodegeneration in HD

描述(申请人提供)：(HD)是最常见的常染色体显性遗传性神经退行性疾病(NDD)，其特征是不自主运动、认知和精神症状，以及无情的疾病进展。HD是由突变的Huntingtin(MHTT)基因的CAG重复扩增引起的，然而HD发病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，包括HD在内的年龄依赖性NDDS的一个特征是早期神经元功能障碍和中枢神经系统突触丢失，随后是进行性神经变性。最近的研究支持补体系统在发育和疾病期间突触修剪中出人意料的作用。在发育过程中，在青光眼小鼠模型中，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“较弱的”或较不活跃的突触被补体“标记”，然后被小胶质细胞消除，小胶质细胞是中枢神经系统中表达吞噬补体受体(即CR3/CD11b)的主要吞噬免疫细胞。我们认为，类似的补体和小胶质细胞依赖机制导致突触丢失，而突触丢失又是HD行为缺陷和选择性神经变性的关键发病机制。在人类HD脑组织和几个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，在全长mHTT HD小鼠模型(BACHD)中，补体因子(C1q和C3)上调并标记了脆弱脑区(即纹状体)中的突触丢失。杨氏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-纹状体神经元之间的相互作用。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丢失参与HD发病的早期阶段，这是HD小鼠皮质纹状体神经元活性降低的结果。为了验证这一假设，我们将研究由Yang实验室开发的创新的条件性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，以及光遗传恢复神经元活动或基于遗传减少/治疗性抗体抑制补体级联(C3和C1q)是否可以改善HD小鼠的突触丢失、神经变性和行为障碍。我们的研究可以证实补体级联(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治疗中抑制这一途径提供支持。

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.