Wakita Masahiro, Yaguchi Hiroaki, Otuski Mika, Tanikawa Satoshi, Miki Yasuo, Aiba Ikuko, Yoshida Mari, Nomura Taichi, Uwatoko Hisashi, Mito Yasunori, Sinpo Kazuyoshi, Ikeuchi Takeshi, Tanaka Shinya, Wakabayashi Koichi, Yabe Ichiro
Department of Neurology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Graduate School of Health Sciences, Hokkaido University, Sapporo, Japan.
Neuropathology. 2025 Apr;45(2):140-152. doi: 10.1111/neup.13009. Epub 2024 Oct 31.
Clinical diagnosis of progressive supranuclear palsy (PSP) is difficult due to various phenotypes. Neuropathologically, PSP is defined by neuronal loss in the basal ganglia and brainstem with widespread occurrence of neurofibrillary tangles (NFTs) and accumulation of phosphorylated tau protein in neurons and glial cells in the brain. We previously identified the point mutation p.Pro3866Ala in the Bassoon (BSN) gene in a Japanese family with PSP-like syndrome. We newly detected BSN mutations in two autopsied PSP cases carrying p.Thr2542Met and p.Glu2759Gly, respectively. The case with p.Thr2542Met mutation showed neurological symptoms including behavioral abnormalities, cognitive dysfunction, and parkinsonism. Brain magnetic resonance imaging (MRI) showed atrophy of the midbrain tegmentum and hippocampus. Pathologically, moderate to severe loss of neurons with gliosis was also found in the substantia nigra, and there was an almost complete loss of neurons with gliosis in the transitional zone of the cornu ammonis (CA) 1 region to the subiculum. NFTs were observed in the globus pallidus, subthalamic nucleus, substantia nigra, and CA1. 4R tau-dominant tauopathy was detected. The case with p.Glu2759Gly mutation showed neurological symptoms, including right-dominant motor impairment, right limping gait, postural instability, and cognitive dysfunction. Brain MRI showed mild atrophy of the midbrain tegmentum and left-dominant parietal lobe atrophy. Pathologically, NFTs were detected in the globus pallidus, subthalamic nucleus, substantia nigra, thalamus, putamen, and brainstem tegmentum. Most neurons were immunopositive for four-repeat tau, whereas only a few of them harbored three-repeat tau-positive NFTs in the hippocampus. We showed the results of a pathological study of PSP cases with BSN mutations; these were two new cases. The clinical phenotypes were similar to the first case in the point of neurological symptoms. Accumulation of four-repeat tau was dominant. Further autopsies of BSN mutation cases and further elucidation of the molecular biological mechanism are desirable.
由于存在多种表型，进行性核上性麻痹（PSP）的临床诊断较为困难。在神经病理学上，PSP的定义是基底神经节和脑干中的神经元丢失，同时大脑中的神经元和神经胶质细胞广泛出现神经原纤维缠结（NFTs）以及磷酸化tau蛋白的积累。我们之前在一个患有PSP样综合征的日本家族中鉴定出巴松管（BSN）基因中的p.Pro3866Ala点突变。我们新检测到两例分别携带p.Thr2542Met和p.Glu2759Gly突变的PSP尸检病例中的BSN突变。携带p.Thr2542Met突变的病例表现出包括行为异常、认知功能障碍和帕金森综合征等神经症状。脑磁共振成像（MRI）显示中脑被盖和海马萎缩。病理检查发现黑质中度至重度神经元丢失并伴有胶质增生，在海马角（CA）1区至下托的过渡区几乎完全是神经元丢失并伴有胶质增生。在苍白球、丘脑底核、黑质和CA1区观察到NFTs。检测到以4R tau为主的tau蛋白病。携带p.Glu2759Gly突变的病例表现出神经症状，包括以右侧为主的运动障碍、右侧跛行步态、姿势不稳和认知功能障碍。脑MRI显示中脑被盖轻度萎缩和以左侧为主的顶叶萎缩。病理检查发现苍白球、丘脑底核、黑质、丘脑、壳核和脑干被盖中有NFTs。大多数神经元对四重复tau蛋白呈免疫阳性，而在海马中只有少数神经元含有三重复tau蛋白阳性的NFTs。我们展示了PSP病例伴有BSN突变的病理研究结果；这是两例新病例。临床表型在神经症状方面与首例病例相似。四重复tau蛋白的积累占主导。需要对BSN突变病例进行更多尸检并进一步阐明分子生物学机制。
