Hoq Md Rejaul, Bharath Sakshibeedu R, Hallinan Grace I, Fernandez Anllely, Vago Frank S, Ozcan Kadir A, Li Daoyi, Garringer Holly J, Vidal Ruben, Ghetti Bernardino, Jiang Wen
bioRxiv. 2023 Jan 23:2023.01.09.523314. doi: 10.1101/2023.01.09.523314.
The Microtubule-Associated Protein Tau (MAPT) is one of the proteins that are central to neurodegenerative diseases. The nature of intracellular tau aggregates is determined by the cell types whether neuronal or glial, the participating tau isoforms, and the structure of the amyloid filament. The transmembrane protein 106B (TMEM106B) has recently emerged as another significant player in neurodegeneration and aging. In the central nervous system, the composition of the gray and white matter differs considerably. The gray matter consists of nerve cell bodies, dendrites, unmyelinated axons, synaptic terminals, astrocytes, oligodendrocytes (satellite cells) and microglia. The white matter differs from the gray for the presence of axonal tracts as the only neuronal component and for the absence of nerve cell bodies, dendrites and synaptic terminals. Cryogenic electron microscopy (cryo-EM) studies have unveiled the structure of tau and TMEM106B, from the cerebral cortex, in several neurodegenerative diseases; however, whether tau and TMEM106B filaments from the gray and white matter share a common fold requires additional investigation.
We isolated tau and TMEM106B from the cerebral cortex and white matter of the frontal lobes of two individuals affected by multiple system tauopathy with presenile dementia (MSTD), a disease caused by the intron 10 mutation +3. We used immunostaining, biochemical, genetics and cryo-EM methods to characterize tau and TMEM106B.
We determined that tau filaments in the gray and the white matter of MSTD individuals can induce tau aggregation and have identical AGD type 2 folds. TMEM106B amyloid filaments were also found in the gray and white matter of MSTD; the filament folds were identical in the two anatomical regions.
Our findings show for the first time that in MSTD two types of amyloid filaments extracted from the gray matter have identical folds to those extracted from the white matter. Whether in this genetic disorder there is a relationship in the pathogenesis of the tau and TMEM106B filaments, remains to be determined. Furthermore, additional studies are needed for other proteins and other neurodegenerative diseases to establish whether filaments extracted from the gray and white matter would have identical folds.
微管相关蛋白Tau（MAPT）是神经退行性疾病的核心蛋白之一。细胞内tau聚集体的性质取决于细胞类型（神经元或神经胶质细胞）、参与的tau异构体以及淀粉样纤维的结构。跨膜蛋白106B（TMEM106B）最近已成为神经退行性变和衰老中的另一个重要因素。在中枢神经系统中，灰质和白质的组成差异很大。灰质由神经细胞体、树突、无髓轴突、突触终末、星形胶质细胞、少突胶质细胞（卫星细胞）和小胶质细胞组成。白质与灰质的不同之处在于存在作为唯一神经元成分的轴突束，且不存在神经细胞体、树突和突触终末。低温电子显微镜（cryo-EM）研究揭示了几种神经退行性疾病中来自大脑皮质的tau和TMEM106B的结构；然而，来自灰质和白质的tau和TMEM106B纤维是否具有共同的折叠结构仍需进一步研究。
我们从两名患有早老性痴呆的多系统tau病（MSTD）患者（一种由内含子10突变+3引起的疾病）额叶的大脑皮质和白质中分离出tau和TMEM106B。我们使用免疫染色、生化、遗传学和低温电子显微镜方法来表征tau和TMEM106B。
我们确定MSTD患者灰质和白质中的tau纤维可诱导tau聚集，并且具有相同的AGD 2型折叠结构。在MSTD患者的灰质和白质中也发现了TMEM106B淀粉样纤维；这两个解剖区域的纤维折叠结构相同。
我们的研究结果首次表明，在MSTD中，从灰质中提取的两种类型的淀粉样纤维与从白质中提取的淀粉样纤维具有相同的折叠结构。在这种遗传疾病中，tau和TMEM106B纤维的发病机制是否存在关联仍有待确定。此外，对于其他蛋白质和其他神经退行性疾病，还需要进行更多研究，以确定从灰质和白质中提取的纤维是否具有相同的折叠结构。
