Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model
Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model
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DOI：
10.1073/pnas.0406361102
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发表时间：
2005-01-04
影响因子：
11.1
通讯作者：
Trojanowski, JQ
中科院分区：
文献类型：
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作者：
Zhang, B;Maiti, A;Trojanowski, JQ
我们测试了以下假设：微管（MT）结合药物可以通过功能性取代MT结合蛋白tau而在tau蛋白病中具有治疗益处，所述MT结合蛋白tau被隔离到人tau蛋白病及其转基因小鼠模型的内含物中。转基因小鼠每周腹腔注射10或25 mg/m2紫杉醇（Paxceed），治疗12周。与假处理相比，两种剂量都恢复了脊髓轴突中的快速轴突运输，其中MT数量和稳定（脱酪氨酸）微管蛋白增加，并且只有Paxceed改善了tau转基因小鼠的运动障碍。因此，MT稳定药物可能具有治疗神经退行性tau蛋白病的治疗潜力，其通过抵消由这种MT稳定蛋白螯合到丝状包涵体中导致的tau功能丧失来治疗。
We tested the hypothesis that microtubule (MT)-binding drugs could be therapeutically beneficial in tauopathies by functionally substituting for the MT-binding protein tau, which is sequestered into inclusions of human tauopathies and transgenic mouse models thereof. Transgenic mice were treated for 12 weeks with weekly i.p. injections of 10 or 25 mg/m(2) paclitaxel (Paxceed). Both doses restored fast axonal transport in spinal axons, wherein MT numbers and stable (detyrosinated) tubulins were increased, compared with sham treatment, and only Paxceed ameliorated motor impairments in tau transgenic mice. Thus, MT-stabilizing drugs could have therapeutic potential for treating neurodegenerative tauopathies by offsetting losses of tau function that result from the sequestration of this MT-stabilizing protein into filamentous inclusions.