Kumada S, Hayashi M, Mizuguchi M, Nakano I, Morimatsu Y, Oda M
Department of Clinical Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Fuchu-shi, Japan.
Acta Neuropathol. 2000 Jan;99(1):48-54. doi: 10.1007/pl00007405.
We examined the mechanism of cerebellar degeneration in brains obtained at autopsy from six cases of hereditary dentatorubral-pallidoluysian atrophy (DRPLA) and six cases of Machado-Joseph disease (MJD), using terminal deoxynucleotidyltransferase-mediated in situ nick end labeling (TUNEL) and immunohistochemistry for apoptosis-related proteins, neurotrophin receptors and glutamate transporters. In three subjects with DRPLA, who developed dementia and cerebellar ataxia at over 50 years of age, the number of Purkinje cells was mildly reduced, TUNEL-positive cells were observed in the molecular layer of the cerebellar cortex, and immunoreactivities for calbindin D28K and excitatory amino acid transporter-1 (EAAT1) were altered in the molecular layer. In addition, all cases of DRPLA showed a reduction of immunoreactivity for EAAT1 in the dentate nucleus. In MJD, augmentation of Bcl-x expression by the Purkinje cells, and increases in Trk B- and GFAP-immunopositive glial cells in the granular layer were observed in half of the cases, whereas immunoreactivity for EAAT-1 was preserved both in the cerebellar cortex and dentate nucleus. One case of MJD showed TUNEL-positive granular cells in the cerebellar cortex. Age-matched control subjects did not show TUNEL-positive cells or immunohistochemical changes in the cerebellum. There were neither TUNEL-positive cells nor alteration of the in situ expression of apoptosis-related proteins in the dentate nucleus in either variant of hereditary spinocerebellar degeneration, although both exhibited grumose degeneration in the dentate nucleus. These findings indicate that latent degeneration in the cerebellar cortex may occur in DRPLA and MJD, in addition to the dentate change, which is the cardinal feature in the neuropathology of these two diseases. The lesion of Purkinje cells and their processes in the molecular layer associated with altered glutamate transport may be important in DRPLA, while the significance of the abnormalities observed in some MJD cases, which might be related to apoptotic mechanism, remains unclear.
我们运用末端脱氧核苷酸转移酶介导的原位缺口末端标记法（TUNEL）以及针对凋亡相关蛋白、神经营养因子受体和谷氨酸转运体的免疫组织化学方法，对6例遗传性齿状核红核苍白球路易体萎缩症（DRPLA）和6例马查多-约瑟夫病（MJD）尸检获得的大脑中小脑变性的机制进行了研究。在3例50岁以上出现痴呆和小脑共济失调的DRPLA患者中，浦肯野细胞数量轻度减少，在小脑皮质分子层观察到TUNEL阳性细胞，分子层中钙结合蛋白D28K和兴奋性氨基酸转运体-1（EAAT1）的免疫反应性发生改变。此外，所有DRPLA病例齿状核中EAAT1的免疫反应性均降低。在MJD中，半数病例观察到浦肯野细胞Bcl-x表达增加，颗粒层中Trk B和胶质纤维酸性蛋白（GFAP）免疫阳性胶质细胞增多，而小脑皮质和齿状核中EAAT-1的免疫反应性均得以保留。1例MJD患者小脑皮质中出现TUNEL阳性颗粒细胞。年龄匹配的对照受试者小脑未显示TUNEL阳性细胞或免疫组织化学变化。在这两种遗传性脊髓小脑变性变体中，尽管齿状核均出现颗粒状变性，但齿状核中既无TUNEL阳性细胞，也无凋亡相关蛋白原位表达的改变。这些发现表明，除了齿状核改变这两种疾病神经病理学的主要特征外，DRPLA和MJD中可能还会发生小脑皮质的潜在变性。与谷氨酸转运改变相关的分子层中浦肯野细胞及其突起的病变在DRPLA中可能很重要，而在一些MJD病例中观察到的异常（可能与凋亡机制有关）的意义尚不清楚。
