Li M, Nakagomi Y, Kobayashi Y, Merry D E, Tanaka F, Doyu M, Mitsuma T, Hashizume Y, Fischbeck K H, Sobue G
Department of Neurology, Nagoya University School of Medicine, Japan.
Am J Pathol. 1998 Sep;153(3):695-701. doi: 10.1016/S0002-9440(10)65612-X.
Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of nuclear inclusions of spinal and bulbar muscular atrophy. Nuclear inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar nuclear inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of AR-positive granular material without limiting membrane, both in the neural and nonneural inclusions. These findings indicate that nuclear inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural nuclear inclusions.
脊髓延髓性肌萎缩症是一种X连锁的运动神经元病，由雄激素受体（AR）基因编码区不稳定的CAG重复序列扩增引起。已证实在脊髓延髓性肌萎缩症患者的脊髓运动神经元中存在突变AR蛋白的核内包涵体（Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: 脊髓延髓性肌萎缩症中的核内包涵体。《神经病学纪事》1998年（即将发表））。在本研究中，我们展示了脊髓延髓性肌萎缩症核内包涵体的组织特异性分布、免疫化学特征和精细结构。在受影响的脊髓和脑干运动神经元中观察到核内包涵体，但在其他未受影响的神经组织中未观察到。在包括阴囊皮肤、真皮、肾脏、心脏和睾丸在内的非神经组织中也出现了类似的核内包涵体，但在脾脏、肝脏和肌肉中未出现。这些包涵体具有相似的表位特征，仅能被识别AR蛋白N端一小部分的抗体检测到，并且它们被泛素化。电子显微镜免疫组织化学显示，在神经和非神经包涵体中，均存在无界膜的AR阳性颗粒物质致密聚集体。这些发现表明，AR蛋白的核内包涵体不仅存在于脊髓延髓性肌萎缩症中发生变性的神经元中，也存在于某些非神经组织中，提示神经和非神经核内包涵体的形成存在共同机制。
