Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in MAPT and one case of sporadic GGT (sGGT) and one case of GGT linked to MAPT K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to MAPT P301T mutation, astrocyte markers GFAP, ALDH1L1, YKL40 mRNA and protein, GJA1 mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers OLIG1 and OLIG2mRNA, and myelin-related genes MBP, PLP1, CNP, MAG, MAL, MOG, and MOBP are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to MAPT K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to MAPT P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to MAPT P301T, sGGT, and GGT linked to MAPT K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time- and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates.

中文翻译：

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与MAPT突变相关的家族性球状神经胶质牛头皮病：分子神经病理学和原型神经元和神经胶质牛头皮病混合的播种能力。

球状胶质牛磺酸病（GGT）是一种涉及灰质和白质（WM）的进行性神经退行性疾病，其特征在于神经元和神经胶质细胞中形成典型的球状星形胶质细胞和少突胶质细胞的过度磷酸化，异常构象，截短的寡聚4Rtau的神经元沉积。夹杂物（分别为GAI和GOI）和盘绕体。为了比较，目前的研究集中于来自两个不相关家族的基因遗传GGT病例，这两个家族在MAPT中携带P301T突变，一例散发性GGT（sGGT），另一例与MAPT K317M突变相关的GGT。携带相同突变的患者，甚至在同一个家庭的携带者中，磷酸化tau蛋白的临床和神经病理学表现以及生化特征都会发生个体差异，而与发病年龄，性别，和疾病的持续时间。免疫组织化学，蛋白质印迹，转录组学，蛋白质组学和磷酸化蛋白质组学以及脑匀浆向野生型（WT）小鼠的脑内接种是方法。在与MAPT P301T突变相关的GGT病例中，星形胶质细胞标志物GFAP，ALDH1L1，YKL40 mRNA和蛋白，GJA1 mRNA和AQ4蛋白显着增加；谷氨酸转运蛋白GLT1（EAAT2）和葡萄糖转运蛋白（SLC2A1）下降；额叶皮层（FC）中的GAI中几乎不存在线粒体丙酮酸载体1（MPC1），并且线粒体解偶联蛋白5（UCP5）几乎不存在。WM中少突胶质细胞标记OLIG1和OLIG2mRNA的表达以及髓磷脂相关基因MBP，PLP1，CNP，MAG，MAL，MOG和MOBP的表达明显降低；CNPase，PLP1和MBP抗体显示髓鞘纤维的减少和破坏。SMI31抗体标记WM中的轴突损伤。在sGGT和与MAPT K317M突变相关的GGT中，也观察到了AQ4，GLUC-t和GLT-1的表达改变。这些改变指向GGT中的原发性星形胶质细胞病变和少突胶质细胞病变。此外，与MAPT P301T突变蛋白型相关的GGT还揭示了由于FC和WM中广泛的（磷酸）蛋白组脱位而引起的蛋白静态失衡，从而触发了神经元投射形态发生和突触传递的破坏。杂色蛋白超磷酸化的鉴定引起了GGT发病机理中仅磷酸化tau蛋白改变的概念的质疑。最后，单侧接种海马体，call体中与MAPT P301T，sGGT和与MAPT K317M突变相关的GGT所产生的GGT均质蛋白的Sarkosyl不溶级分，在野生型小鼠体内，如果没有任何GAI和GOI，而只有螺旋状体，则在磷酸化，非寡聚和非截短的4Rtau和3Rtau上产生种子，并随时间和区域而定地扩散。这些实验证明，宿主tau菌株在调节细胞易损性和磷酸化tau聚集体的表型方面很重要。