the role of molecular chaperones in α-synuclein-related diseases

14-3-3蛋白是一种新型的分子伴侣，识别多种靶蛋白的含磷酸丝氨酸基序，调节多种类型的信号转导途径。我们已经报道了14-3-3免疫反应定位于帕金索病和多系统萎缩患者脑内含α突触核蛋白的包涵素。然后，我们对人α-突触核蛋白(A53T)转基因小鼠的脑和脊髓进行了检测，发现α-突触核蛋白和14-3-3蛋白在免疫组织化学中共存。我们还观察到一些热休克蛋白在突触核病患者脑组织中的免疫反应增强。此外，我们利用肌萎缩侧索硬化症(ALS)患者的尸检脊髓进行了14-3-3蛋白的免疫组织化学研究，发现散发性和家族性ALS患者的路易体样透明质包涵体中都有14-3-3免疫反应阳性。我们还观察到14-3-3免疫反应定位于人SOD1G93T转基因小鼠的前角细胞内含α突触核蛋白的包含素。此外，我们还发现14-3-3在多发性硬化症和进行性多灶性白质脑病患者的脱髓鞘皮损、CreutzFeldt-Jakob病患者的皮质和皮质下皮损以及Binswanger病患者的缺血白质皮损中的星形胶质细胞免疫表达增强。这些结果表明，14-3-3蛋白可能在神经退行性疾病患者脑内多种包涵体的形成中起重要作用，14-3-3蛋白可能在脱髓鞘、炎症和缺血等多种病理条件下在星形胶质细胞中诱导表达，并可能与星形胶质细胞增生症的形成有关。

14-3-3 proteins, a novel type of molecular chaperons, recognizes the phosphoserine-containing motifs of several target proteins, and regulates various types of signal transduction pathways. We have already reported that 14-3-3 immunoreactivity was localized to the α-synuclein-containing inclusins in brains with Parkinso's disease and multiple system atrophy. We then examined the brains and spinal cords of human α-synuclein (A53T) transgenic mice, and found the immunohistochemical colocalization of α-synuclein and 14-3-3 proteins. We also observed the increased immunoreactivities for some heat shock proteins in brains with synucleinopathies. Furthermore, we performed immunohistochemical studies on 14-3-3 proteins using autopsied spinal cord from patients with amyotrophic lateral sclerosis (ALS), and found 14-3-3 immunoreactivity in the Lewy body-like hyaline inclusions from both sporadic and familial ALS cases. We also observed that 14-3-3 immunoreactivity was localized to the α-synuclein-containing inclusinsin in the anterior horn cells from human SOD1(G93T) trausgenic mice. Moreover, we found the enhanced astroglial immunoexpression of 14-3-3 in the demyelinated lesions from patients with multiple sclerosis and progressive multifocal leukoencephalopathy, and in the cortical and subcortical lesions from patients with Creutzfeldt-Jakob disease, and in the ischemic white matter lesions from Binswanger's disease cases. These data suggest that 14-3-3 proteins may play an important role in the formation of several types of inclusions in brains with neurodegenerative diseases, and that 14-3-3 proteins may be induced in astrocytes under various kinds of pathological conditions, including demyelination, inflammation, and ischemia, and may be associated with the formation of astrogliosis.