Kim T W, Wu K, Xu J L, Black I B
Program in Physiology and Neurobiology, Rutgers State University of New Jersey, Piscataway.
Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11642-4. doi: 10.1073/pnas.89.23.11642.
Duchenne muscular dystrophy (DMD) is a common, lethal, chromosome X-linked inherited disease. Moderate cognitive impairment is a feature of DMD, but the underlying mechanisms are unknown. DMD is characterized by a defect in a protein, dystrophin, that is located predominantly in muscle but has been detected in brain. We sought to directly localize dystrophin within the complex synaptic structure of the cerebral cortex by focusing on the postsynaptic density (PSD), which appears to be central to synaptic function. We report that a specific anti-dystrophin antibody (anti 6-10) recognizes three distinct proteins in the purified PSD: the 400-kDa dystrophin and two previously unidentified dystrophin-related proteins of 120 and 110 kDa. These proteins exhibited differential regional expression in PSDs from cerebral cortex, cerebellum, and olfactory bulb. In the cortical PSD, the 400-kDa dystrophin was predominant, whereas the 120-kDa protein was the major species in cerebellum and olfactory bulb PSDs. The three proteins were differentially expressed in the PSD during cortical development: the 400-kDa protein exhibited a selective 9-fold increase during postnatal days 7 to 10, suggesting a normal physiological role in synaptic maturation. The PSD from the mdx mouse, a model of human DMD, contained no detectable 400-kDa dystrophin but expressed the two dystrophin-related proteins. Our results indicate that brain dystrophins are localized to the PSD, potentially as three isoforms, and raise the possibility that cognitive abnormalities in DMD are attributable to synaptic dysfunction associated with deficits in brain dystrophin molecules.
杜氏肌营养不良症（DMD）是一种常见的、致命的、X染色体连锁的遗传性疾病。中度认知障碍是DMD的一个特征，但其潜在机制尚不清楚。DMD的特征是一种蛋白质——抗肌萎缩蛋白存在缺陷，该蛋白主要位于肌肉中，但在大脑中也有检测到。我们试图通过聚焦于突触后致密部（PSD）来直接将抗肌萎缩蛋白定位在大脑皮层复杂的突触结构内，而PSD似乎是突触功能的核心。我们报告一种特异性抗肌萎缩蛋白抗体（抗6 - 10）在纯化的PSD中识别出三种不同的蛋白质：400 kDa的抗肌萎缩蛋白以及两种先前未鉴定的120 kDa和110 kDa的抗肌萎缩蛋白相关蛋白。这些蛋白质在大脑皮层、小脑和嗅球的PSD中呈现出不同的区域表达。在皮层PSD中，400 kDa的抗肌萎缩蛋白占主导，而120 kDa的蛋白是小脑和嗅球PSD中的主要种类。这三种蛋白质在皮层发育过程中的PSD中差异表达：400 kDa的蛋白在出生后第7至10天有选择性地增加了9倍，表明其在突触成熟中具有正常的生理作用。来自mdx小鼠（人类DMD模型）的PSD中未检测到400 kDa的抗肌萎缩蛋白，但表达了两种抗肌萎缩蛋白相关蛋白。我们的结果表明，大脑中的抗肌萎缩蛋白可能以三种异构体的形式定位于PSD，并增加了DMD认知异常归因于与大脑抗肌萎缩蛋白分子缺陷相关的突触功能障碍的可能性。
