Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, The Netherlands.
J Pathol. 2012 Jan;226(1):132-42. doi: 10.1002/path.2984. Epub 2011 Oct 18.
Alzheimer's disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and Pick's disease (PiD) are commonly known as tauopathies. Neurodegeneration observed in these diseases is linked to neuronal fibrillary hyperphosphorylated tau protein inclusions. Transglutaminases (TGs) are inducible enzymes, capable of modifying conformational and/or structural properties of proteins by inducing molecular cross-links. Both transglutaminase 1 (TG1) and transglutaminase 2 (TG2) are abundantly expressed in the brain and are associated with fibrillary hyperphosphorylated tau protein inclusions in neurons of AD, so-called neurofibrillary tangles (NFTs). However, other data obtained by our group suggested that tau pathology in the brain may be primarily related to TG1 and not to TG2 activity. To obtain more information on this issue, we set out to investigate the association of TG1, TG2, and TG-catalysed cross-links with fibrillary hyperphosphorylated tau inclusions in tauopathies other than AD, using immunohistochemistry. We found strong TG1 and TG-catalysed cross-link staining in neuronal tau inclusions characteristic of PSP, FTDP-17 with mutations in the tau gene (FTDP-17T), and PiD brain, whereas, in contrast to AD, TG2 was only rarely observed in these inclusions. Furthermore, using a biochemical approach, we demonstrated that tau is a substrate for TG1-mediated cross-linking. Interestingly, we found co-localization of the TG1 activator, tazarotene-induced gene 3 (TIG3), in the neuronal tau inclusions of PSP, FTDP-17T, and PiD, but not in NFTs of AD cases, indicating that these tau-containing protein aggregates are not identical. We conclude that TG1-catalysed cross-linking, regulated by TIG3, might play an important role in the formation of neuronal tau inclusions in PSP, FTDP-17T, and PiD brain.
阿尔茨海默病（AD）、进行性核上性麻痹（PSP）、额颞叶痴呆伴 17 号染色体相关帕金森病（FTDP-17）和皮克病（PiD）通常被称为 tau 病。这些疾病中观察到的神经退行性变与神经元纤维状过度磷酸化 tau 蛋白包涵体有关。转谷氨酰胺酶（TGs）是诱导酶，能够通过诱导分子交联来修饰蛋白质的构象和/或结构特性。转谷氨酰胺酶 1（TG1）和转谷氨酰胺酶 2（TG2）在大脑中均大量表达，并与 AD 神经元中的纤维状过度磷酸化 tau 蛋白包涵体（即神经原纤维缠结，NFTs）有关。然而，我们小组获得的其他数据表明，大脑中的 tau 病理学可能主要与 TG1 而非 TG2 活性有关。为了获得更多关于这个问题的信息，我们着手使用免疫组织化学方法研究 TG1、TG2 和 TG 催化的交联与 AD 以外的 tau 病中纤维状过度磷酸化 tau 包涵体的关系。我们发现，在 PSP、tau 基因突变所致 FTDP-17（FTDP-17T）和 PiD 大脑中具有特征性神经元 tau 包涵体的 tau 中，TG1 和 TG 催化的交联染色强烈，而与 AD 相反，TG2 在这些包涵体中很少观察到。此外，使用生化方法，我们证明 tau 是 TG1 介导的交联的底物。有趣的是，我们发现 TG1 激活剂 tazarotene-induced gene 3（TIG3）在 PSP、FTDP-17T 和 PiD 的神经元 tau 包涵体中存在共定位，但在 AD 病例的 NFT 中不存在，表明这些包含 tau 的蛋白聚集体并不相同。我们得出结论，由 TIG3 调节的 TG1 催化交联可能在 PSP、FTDP-17T 和 PiD 大脑中神经元 tau 包涵体的形成中发挥重要作用。
