Pathophysiology of spinocerebellar degeneration /retinitis pigmentosa linked to a point mutation of alpha-tocopherol transfer protein gene

研究了第一例与α -生育酚转移蛋白（aTTP）基因编码突变相关的进行性共济失调和视网膜色素变性的尸检病例。除了视网膜病变和脊髓后柱的死背型变性外，与维生素E缺乏的病例或动物模型中报道的情况相当，小脑皮质也有轻度变性。建立aTTP缺失小鼠模型，除脊髓后柱病变外，脊髓前角细胞内脂褐素大量堆积。由于这些脊髓损伤分别因过量摄入或缺乏维生素ine而加重或减轻，因此TTP基因缺失的影响是通过降低组织中维生素ine浓度来介导的。另一方面，上述尸检病例的小脑中维生素E的浓度在长期服用维生素E后，除小脑外，其余部分都是正常的。如果维生素E在小脑中的代谢途径不同，则可能是aTTP基因突变影响了它，导致小脑变性。由于缺失一个TTP基因的模型小鼠没有检测到类似的小脑损伤，因此需要进一步研究涉及aTTP的分子通路及其区域差异。其他来源的遗传性共济失调也进行了研究，特别注意神经元核内包涵体（NIIs）。在包括各种CAG重复疾病和神经元核内透明蛋白包涵病（NIHID）在内的一系列尸检脑中，研究了ataxin-2， -3的免疫定位。结果发现，在NIIs中存在的ataxin-2或-3分别不是SCA2或SCA3所特有的。我们发明了双标记免疫荧光双强化技术，现已被证明对免疫组织化学非常有效，适用于多种疾病，包括维生素e和aTTP异常。

The first autopsy case with progressive ataxia and retinitis pigmentosa associated with a mutation of the gene coding for alpha-tocopherol transfer protein (aTTP) was investigated. In addition to retinal lesion and dying-back type degeneration in the posterior column of the spinal cord, comparable to those reported in cases or animal model with deficiency of vitamin E, mild degeneration was noted in the cerebellar cortex. Mouse model with deleted aTTP was generated, where massive accumulation of lipofuscin was noted in the anterior horn cells of the spinal cord in addition to posterior column lesion. Because these spinal lesions were exaggerated or attenuated by excess intake or deficiency of vitaminE, respectively, effects of deleted a TTP gene is mediated by lowered vitaminE concentration in the tissue. On the other hand, vitaminE concentration in the cerebellum of the autopsy case mentioned above is normalized except for the cerebellum after long term administration of vitamin E.If the metabolic pathway of vitamin E in the cerebellum is different, a mutation of aTTP gene may have affected it and lead to cerebellar degeneration. Because similar cerebellar lesion was not detectable in model mice with deleted a TTP gene, molecular pathway involving aTTP and its regional difference should be further investigated. Hereditary ataxias of other origins were also investigated with special attention to neuronal intranuclear inclusions (NIIs). Immunolocalization of ataxin-2, -3 was investigated in a series of autopsy brains including various CAG repeat disorders and neuronal intranuclear hyaline inclusion disease (NIHID). It was found that the presence of ataxin-2 or -3 in the NIIs was not specific for SCA2 or SCA3, respectively. We invented dual intensification technique for double-labeled immunofluorescence, which is now proved to be very effective for immunohistochemistry applicable to a wide range of disorders including vitamineE and aTTP abnormality.