Nature Chemical Biology：一种可助治疗老年痴呆症的酶抑制剂

加拿大研究人员研究发现使用一种酶抑制剂可阻止tau蛋白中糖类的去除，或可有利于老年痴呆症的治疗。这项发现为我们对老年痴呆症的内在研究提供了新见解。该研究发表于本月出版的《自然—化学生物学》上。

老年痴呆症的症状表现为失忆和精神错乱。从细胞层面上来看，该病的特点则是tau蛋白不断累积，直至形成较大纤维。许多研究老年痴呆症的科学家往往试图找到能直接与这些纤维进行反应的分子，分解或者阻碍纤维的形成，从而治疗此病。不过，目前还不清楚是什么物质控制着这些纤维的形成；一旦找到纤维的前期形成因素，那么，老年痴呆症防治的早期干预将成为可能。

David Vocadlo和同事将糖基转移酶（OGT）的抑制剂Thiamet-G注入患有老年痴呆症的转基因小鼠体内后，发现tau蛋白累积速度减慢，神经细胞缺失开始减少。特别是抑制剂成功阻止了酶将tau蛋白中的糖类去除；实验检测也证明这些糖类能直接减慢纤维的形成。（生物谷 bioon.com）

doi:10.1038/nchembio.797
PMC:
PMID:

Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation

Scott A Yuzwa, Xiaoyang Shan, Matthew S Macauley, Thomas Clark, Yuliya Skorobogatko, Keith Vosseller，David J Vocadlo

Oligomerization of tau is a key process contributing to the progressive death of neurons in Alzheimer's disease. Tau is modified by O-linked N-acetylglucosamine (O-GlcNAc), and O-GlcNAc can influence tau phosphorylation in certain cases. We therefore speculated that increasing tau O-GlcNAc could be a strategy to hinder pathological tau-induced neurodegeneration. Here we found that treatment of hemizygous JNPL3 tau transgenic mice with an O-GlcNAcase inhibitor increased tau O-GlcNAc, hindered formation of tau aggregates and decreased neuronal cell loss. Notably, increases in tau O-GlcNAc did not alter tau phosphorylation in vivo. Using in vitro biochemical aggregation studies, we found that O-GlcNAc modification, on its own, hinders tau oligomerization. O-GlcNAc also inhibits thermally induced aggregation of an unrelated protein, TAK-1 binding protein, suggesting that a basic biochemical function of O-GlcNAc may be to prevent protein aggregation. These results also suggest O-GlcNAcase as a potential therapeutic target that could hinder progression of Alzheimer's disease.