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

对首例因α-生育酚转移蛋白(ATTP)基因突变导致进行性共济失调和视网膜色素变性的尸检病例进行了研究。除了视网膜损害和脊髓后柱的死亡型变性外，与文献报道的维生素E缺乏病例或动物模型相似，小脑皮质也有轻微的变性。建立aTTP缺失的小鼠模型，除脊髓后柱损伤外，脊髓前角细胞内可见大量脂褐素积聚。由于这些脊柱损伤分别因维生素摄入过多或不足而被夸大或减弱，因此缺失TTP基因的影响是通过降低组织中的维生素浓度来实现的。另一方面，上述尸检病例在长期服用维生素E后，除小脑外，小脑中的维生素E浓度均恢复正常。如果小脑中维生素E的代谢途径不同，则可能是aTTP基因突变影响了小脑，导致小脑退变。由于在TTP基因缺失的模型小鼠中未检测到类似的小脑损害，涉及aTTP的分子途径及其区域差异有待进一步研究。对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)。研究了ataxin-2、-3在一系列尸检脑组织中的免疫定位，包括各种CAG重复序列障碍和神经元核内透明质包涵体病(NIHID)。发现NIIS中ataxin-2和-3的存在分别不是SCA2和SCA3所特有的。我们发明了双标记免疫荧光双重增强技术，现已被证明是非常有效的免疫组织化学技术，适用于包括维生素E和aTTP异常在内的广泛疾病。

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.