Prominent features of HD neuropathology are the intranuclear and cytoplasmic inclusions of huntingtin and striatal and cortical neuronal cell death. Recently, synaptic defects have been reported on HD-related studies, including impairment of neurotransmitter release and alterations of synaptic components. However, the definite characteristics of synapse dysfunction and the underlying mechanisms remain largely unknown. We studied the gene expression levels and patterns of a number of proteins forming the cytoskeletal matrix of the presynaptic active zones in HD transgenic mice (R6/1), in hippocampal neuronal cultures overexpressing mutant huntingtin and in postmortem brain tissues of HD patients. To investigate the interactions between huntingtin and active proteins, we performed confocal microscopic imaging and immunoprecipitation in mouse and HEK 293 cell line models. The mRNA and protein levels of Bassoon were reduced in mouse and cell culture models of HD and in brain tissues of patients with HD. Moreover, a striking re-distribution of a complex of proteins including Bassoon, Piccolo and Munc 13–1 from the cytoplasm and synapses into intranuclear huntingtin aggregates with loss of active zone proteins and dendritic spines. This re-localization was age-dependent and coincided with the formation of huntingtin aggregates. Using co-immunoprecipitation, we demonstrated that huntingtin interacts with Bassoon, and that this interaction is likely mediated by a third linking protein. Three structural proteins involved in neurotransmitter release in the presynaptic active zones of neurons are altered in expression and that the proteins are redistributed from their normal functional site into mutant huntingtin aggregates.

中文翻译：

---

没有低音管和短笛就没有交响曲：亨廷顿氏病中突触活动区蛋白的变化。

HD神经病理学的突出特征是亨廷顿蛋白的核内和胞质内包涵体以及纹状体和皮质神经元细胞死亡。近来，在HD相关的研究中已经报道了突触缺陷，包括神经递质释放受损和突触成分改变。但是，突触功能障碍的确切特征和潜在的机制仍然很大程度上未知。我们研究了基因表达水平和形成高清转基因小鼠（R6 / 1），过表达突变亨廷顿蛋白的海马神经元培养物和高清患者死后脑组织中突触前活性区细胞骨架基质的许多蛋白质的模式。为了研究亨廷顿蛋白与活性蛋白之间的相互作用，我们在小鼠和HEK 293细胞系模型中进行了共聚焦显微镜成像和免疫沉淀。在小鼠和HD细胞培养模型以及HD患者脑组织中，巴松管的mRNA和蛋白水平降低。此外，包括巴松管，短笛和Munc 13-1在内的蛋白质复合物从细胞质中突然突触分布，并突触形成核内亨廷顿蛋白聚集体，而活性区蛋白和树突棘则丢失。这种重新定位是与年龄有关的，并且与亨廷顿蛋白聚集物的形成相吻合。使用共免疫沉淀，我们证明了亨廷顿蛋白与巴松管相互作用，并且这种相互作用很可能是由第三种连接蛋白介导的。