Canu N, Dus L, Barbato C, Ciotti M T, Brancolini C, Rinaldi A M, Novak M, Cattaneo A, Bradbury A, Calissano P
Dipartimento di Neuroscienze, Università di Roma Tor Vergata, 00173 Roma, Italy.
J Neurosci. 1998 Sep 15;18(18):7061-74. doi: 10.1523/JNEUROSCI.18-18-07061.1998.
Cerebellar granule cells undergo apoptosis in culture after deprivation of potassium and serum. During this process we found that tau, a neuronal microtubule-associated protein that plays a key role in the maintenance of neuronal architecture, and the pathology of which correlates with intellectual decline in Alzheimer's disease, is cleaved. The final product of this cleavage is a soluble dephosphorylated tau fragment of 17 kDa that is unable to associate with microtubules and accumulates in the perikarya of dying cells. The appearance of this 17 kDa fragment is inhibited by both caspase and calpain inhibitors, suggesting that tau is an in vivo substrate for both of these proteases during apoptosis. Tau cleavage is correlated with disruption of the microtubule network, and experiments with colchicine and taxol show that this is likely to be a cause and not a consequence of tau cleavage. These data indicate that tau cleavage and change in phosphorylation are important early factors in the failure of the microtubule network that occurs during neuronal apoptosis. Furthermore, this study introduces new insights into the mechanism(s) that generate the truncated forms of tau present in Alzheimer's disease.
在缺乏钾和血清的情况下，小脑颗粒细胞在培养过程中会发生凋亡。在此过程中，我们发现tau蛋白（一种在维持神经元结构中起关键作用的神经元微管相关蛋白，其病理学与阿尔茨海默病的智力衰退相关）被切割。这种切割的最终产物是一个17 kDa的可溶性去磷酸化tau片段，它无法与微管结合，并在垂死细胞的胞体中积累。半胱天冬酶和钙蛋白酶抑制剂均能抑制这种17 kDa片段的出现，这表明在凋亡过程中tau是这两种蛋白酶在体内的底物。tau的切割与微管网络的破坏相关，秋水仙碱和紫杉醇的实验表明，这可能是tau切割的原因而非结果。这些数据表明，tau的切割和磷酸化变化是神经元凋亡过程中微管网络功能障碍的重要早期因素。此外，本研究为阿尔茨海默病中出现的截短形式的tau的产生机制提供了新的见解。
