School of Medicine, Xi'an Jiao Tong University, Xi'an 710061, P.R. China.
Int J Mol Med. 2012 Sep;30(3):569-78. doi: 10.3892/ijmm.2012.1025. Epub 2012 Jun 12.
Microtubule affinity-regulating kinase 4 (MARK4) belongs to a family of kinases that are able to actively phosphorylate the neuronal microtubule-associate proteins (MAPs), such as tau, MAP2 and the ubiquitous MAP4. Abnormal changes in tubulin and the profiles of tau have been previously reported in the human brain and animal transmissible spongiform encephalopathies (TSEs), which may be associated with abnormal alterations of various cellular kinases. To elucidate the possible role of MARK4 in TSE pathogenesis, the MARK4 levels in the brain tissues of scrapie-infected rodents and human prion diseases were evaluated using western blotting and immunohistochemical assays. The results revealed that at terminal stages of the diseases, MARK4 levels in the brain tissues of the scrapie 263K-infected hamsters, 139A-infected mice and a case of Creutzfeldt-Jakob disease (CJD, G114V gCJD) correlated with amounts of PrP(Sc) deposits that were almost undetectable. On the other hand MARK4 signals were noticeable in the brain tissues of a fatal familial insomnia (FFI) patient without PrP(Sc). The reduction of MARK4 was closely related to the prolonged incubation times. These results could be reproduced in SK-N-SH and PC12 cell lines after being exposed to the synthetic peptide PrP106-126. Accordingly, the levels of phosphorylated tau at Ser262 (p-tau262) in cultured cells exposed to PrP106-126, or the ratios of p-tau262/total tau in the brain tissues of 263K-infected hamsters were also significantly decreased. According to our data there is a correlation between a TSE pathological-associated decline of MARK4 in the brain tissues with the deposits of PrP(Sc). Reduction of MARK4 will result in abnormalities of tau phosphorylation, and possibly induce further detachment of microtubules and hinder microtubule transportation.
微管亲和调节激酶 4（MARK4）属于一组能够积极磷酸化神经元微管相关蛋白（MAPs）的激酶，如 tau、MAP2 和普遍存在的 MAP4。先前在人类大脑和动物传染性海绵状脑病（TSEs）中已经报道了微管和 tau 形态的异常变化，这可能与各种细胞激酶的异常改变有关。为了阐明 MARK4 在 TSE 发病机制中的可能作用，使用 Western 印迹和免疫组织化学检测评估了感染朊病毒的啮齿动物和人类朊病毒病脑组织中的 MARK4 水平。结果表明，在疾病的终末期，感染 scrapie 263K 的仓鼠、感染 139A 的小鼠和一例克雅氏病（G114V gCJD）的脑组织中的 MARK4 水平与 PrP（Sc）沉积物的量相关，这些沉积物几乎无法检测到。另一方面，在没有 PrP（Sc）的致命家族性失眠症（FFI）患者的脑组织中可以看到 MARK4 信号。MARK4 的减少与潜伏期的延长密切相关。这些结果在暴露于合成肽 PrP106-126 后可以在 SK-N-SH 和 PC12 细胞系中重现。因此，暴露于 PrP106-126 的培养细胞中的 tau 在 Ser262 处的磷酸化（p-tau262）水平或感染 263K 的仓鼠脑组织中 p-tau262/总 tau 的比值也显著降低。根据我们的数据，TSE 相关脑组织中 MARK4 的病理下降与 PrP（Sc）的沉积之间存在相关性。MARK4 的减少将导致 tau 磷酸化异常，并可能导致微管进一步脱离和阻碍微管运输。
