Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
Department of Physiology, Seoul National University College of Medicine, Seoul, Korea.
J Korean Med Sci. 2019 Aug 26;34(33):e225. doi: 10.3346/jkms.2019.34.e225.
Tauopathies, a class of neurodegenerative diseases that includes Alzheimer's disease (AD), are characterized by the deposition of neurofibrillary tangles composed of hyperphosphorylated tau protein in the human brain. As abnormal alterations in histone acetylation and methylation show a cause and effect relationship with AD, we investigated the role of several Jumonji domain-containing histone demethylase () genes, which have yet to be studied in AD pathology.
To examine alterations of several genes in AD pathology, we performed bioinformatics analyses of gene expression profiles in brain tissue samples from deceased AD patients. Furthermore, to investigate the possible relationship between alterations in gene expression profiles and AD pathology in vivo, we examined whether tissue-specific downregulation of homologs () can affect tau-induced neurotoxicity using transgenic flies containing the UAS-Gal4 binary system.
The expression levels of , , and were significantly higher in postmortem brain tissue from patients with AD than from non-demented controls, whereas mRNA levels were downregulated in the brains of patients with AD. Using transgenic flies, we revealed that knockdown of (homolog to human ), (homolog to human ), (homolog to human ), or (homolog to human ) genes in the eye ameliorated the tau-engendered defects, resulting in less severe phenotypes. However, kdm4a knockdown in the central nervous system uniquely ameliorated tau-induced locomotion defects by restoring heterochromatin.
Our results suggest that downregulation of expression may be a potential therapeutic target in AD.
tau 病，一类包括阿尔茨海默病（AD）的神经退行性疾病，其特征是在人脑内沉积由过度磷酸化 tau 蛋白组成的神经原纤维缠结。由于组蛋白乙酰化和甲基化的异常改变与 AD 呈因果关系，我们研究了几个包含 Jumonji 结构域的组蛋白去甲基酶（）基因的作用，这些基因在 AD 病理中尚未被研究过。
为了研究几种基因在 AD 病理中的改变，我们对来自已故 AD 患者脑组织样本的基因表达谱进行了生物信息学分析。此外，为了研究基因表达谱改变与体内 AD 病理之间的可能关系，我们使用含有 UAS-Gal4 双元系统的转基因果蝇，研究了组织特异性下调同源物（）是否会影响 tau 诱导的神经毒性。
与非痴呆对照相比，AD 患者死后脑组织中的、和基因表达水平显著升高，而 AD 患者大脑中的基因表达水平下调。通过转基因果蝇，我们揭示了在眼睛中敲低（同源物到人类）、（同源物到人类）、（同源物到人类）或（同源物到人类）基因可改善 tau 引起的缺陷，导致表型较轻。然而，在中枢神经系统中敲低 kdm4a 基因通过恢复异染色质，独特地改善了 tau 诱导的运动缺陷。
我们的结果表明，下调基因表达可能是 AD 的一个潜在治疗靶点。
