Ferrer Isidre, Legati Andrea, García-Monco J Carlos, Gomez-Beldarrain Marian, Carmona Margarita, Blanco Rosa, Seeley William W, Coppola Giovanni
From the Institute of Neuropathology, IDIBELL-Bellvitge University Hospital, University of Barcelona, Hospitalet de Llobregat; CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Spain (IF, MC, RB); Department of Neurology and Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, California (AL, GC); Service of Neurology, Hospital Galdakao-Usansolo, Vizcaya, Spain (JCG-M, MG-B); and Department of Neurology and Pathology, Memory and Aging Center, University of California, San Francisco, California (WWS).
J Neuropathol Exp Neurol. 2015 Apr;74(4):370-9. doi: 10.1097/NEN.0000000000000180.
A familial behavioral variant frontotemporal dementia associated with astrocyte-predominant tauopathy is described in 2 sisters born from consanguineous parents. The neuropathologic examination revealed massive accumulation of abnormally hyperphosphorylated, conformational, truncated tau at aspartic acid 421, ubiquitinated and nitrated tau at Tyr29 in cortical astrocyte (including their perivascular foot processes), and Bergmann glia. Smaller amounts of abnormal tau were observed in neurons and rarely in oligodendrocytes. There was decreased expression of glial glutamate transporter in the majority of tau-positive astrocytes. Gel electrophoresis of sarkosyl-insoluble fractions showed 2 bands of 64 and 60 kDa and a doublet of 67 to 70 kDa (which are different from those seen in Alzheimer disease and in typical 4R and 3R tauopathies) together with several bands of lower molecular weight indicative of truncated tau. Analysis of the expression of MAPT isoforms further revealed altered splicing and representation of tau isoforms involving exons 2, 3, and 10. Genetic testing revealed no known mutations in PSEN1, PSEN2, APP, MAPT, GRN, FUS, and TARDBP and no pathologic expansion in C9ORF72. However, a novel rare heterozygous sequence variant(p.Q140H) of uncertain significance was identified in FUS in both siblings.
在一对近亲父母所生的两姐妹中，描述了一种与以星形胶质细胞为主的tau蛋白病相关的家族性行为变异型额颞叶痴呆。神经病理学检查显示，在皮质星形胶质细胞（包括其血管周围足突）和伯格曼胶质细胞中，异常过度磷酸化、构象改变、截短的天冬氨酸421位点tau蛋白大量积聚，酪氨酸29位点的tau蛋白发生泛素化和硝化。在神经元中观察到少量异常tau蛋白，在少突胶质细胞中则很少见。大多数tau蛋白阳性星形胶质细胞中胶质谷氨酸转运体的表达降低。 Sarkosyl不溶性组分的凝胶电泳显示有64 kDa和60 kDa的两条带以及67至70 kDa的双峰（这与阿尔茨海默病以及典型的4R和3R tau蛋白病中所见的不同），还有几条低分子量带，表明存在截短的tau蛋白。对MAPT异构体表达的分析进一步揭示了涉及外显子2、3和10的tau异构体的剪接和表达改变。基因检测显示PSEN1、PSEN2、APP、MAPT、GRN、FUS和TARDBP中没有已知突变，C9ORF72也没有病理性扩增。然而，在两姐妹的FUS基因中均鉴定出一种意义不确定的新型罕见杂合序列变异（p.Q140H）。
