Korea Institute of Science and Technology (KIST), Brain Science Institute, Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Seoul, 02791, Republic of Korea.
Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
Exp Mol Med. 2018 Apr 6;50(4):1-11. doi: 10.1038/s12276-017-0008-7.
During aggressive tumor growth and migration, glioblastoma cells secrete diverse molecules and adhesion proteins to the extracellular matrix. Yet, the biochemical effects of the glioblastoma secretome in the brain remain largely unknown. Here we show that soluble CD44 secreted from glioblastoma cells induces neuronal degeneration through the activation of tau pathology in the brain. Glioblastoma-xenograft tissues showed a number of degenerating neurons bearing highly phosphorylated tau. Through a series of secretome-analyses, we identified that soluble CD44 was the responsible protein inducing tau phosphorylation and aggregation (EC = 19.1 ng/mL). The treatment of sCD44 to primary hippocampal neurons-induced tau hyperphosphorylation, leading to neuronal degeneration. Also, the injection of sCD44 into the brains of tau transgenic mice induced tau hyper-phosphorylation in hippocampal neurons. Altogether, our data suggest a neurodegenerative role of sCD44 in promoting tau pathology and serving as a molecular link between glioblastoma and neurodegeneration.
在侵袭性肿瘤生长和迁移过程中，胶质母细胞瘤细胞向细胞外基质分泌多种分子和黏附蛋白。然而，胶质母细胞瘤分泌组在大脑中的生化作用在很大程度上仍是未知的。在这里，我们表明，从胶质母细胞瘤细胞分泌的可溶性 CD44 通过激活大脑中的 tau 病理学诱导神经元变性。胶质母细胞瘤异种移植物组织显示出许多具有高度磷酸化 tau 的变性神经元。通过一系列分泌组分析，我们鉴定出可溶性 CD44 是诱导 tau 磷酸化和聚集的负责蛋白（EC = 19.1ng/mL）。sCD44 处理原代海马神经元诱导 tau 过度磷酸化，导致神经元变性。此外，将 sCD44 注射到 tau 转基因小鼠的大脑中诱导海马神经元中的 tau 过度磷酸化。总之，我们的数据表明 sCD44 在促进 tau 病理学方面具有神经退行性作用，并作为胶质母细胞瘤和神经退行性变之间的分子联系。
