Strategies for diminishing katanin-based loss of microtubules in tauopathic neurodegenerative diseases
Strategies for diminishing katanin-based loss of microtubules in tauopathic neurodegenerative diseases
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DOI：
10.1093/hmg/ddq521
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发表时间：
2011-02-15
影响因子：
3.5
通讯作者：
Baas, Peter W.
中科院分区：
文献类型：
--
作者：
Sudo, Haruka;Baas, Peter W.
通常认为，在阿尔茨海默病等疾病中，随着tau与微管的分离，微管逐渐解体。然而，到目前为止，还没有令人信服的证据表明这种解体是由于微管从其末端解聚所致。在最近的研究中，我们已经证明神经元含有足够水平的被称为katanin的微管切断蛋白，如果不以某种方式减弱的话，它可以完全破坏轴突微管阵列。轴突微管上tau的存在使它们对katanin的敏感性显著降低，这促使我们假设，tau病中微管的解体可能是由于微管失去tau而导致的。为了支持这一假设，我们在这里证明了致病tau突变体与微管的结合强度低于野生型tau突变体，对基于katanin的切割提供的保护相应较少。利用培养的大鼠海马神经元，我们探索了两种在tau耗竭条件下加强轴突微管以对抗katanin过度切断的潜在疗法。我们发现，无论是通过过表达HDAC6使微管去乙酰化，还是用NAP(一种微管相互作用的神经保护肽)处理神经元，都能显著保护微管免受基于katanin的丢失。在这两种情况下，我们发现这些治疗也减少了通常伴随tau耗竭而出现的轴突分支的特征性增加，这种影响也被认为与微管的切断直接相关。这些观察结果可能有助于开发治疗方案，以保护微管免受肌萎缩症患者轴突丢失的影响。
It is commonly stated that microtubules gradually disintegrate as tau becomes dissociated from them in tauopathies such as Alzheimer's disease. However, there has been no compelling evidence to date that such disintegration is due to depolymerization of microtubules from their ends. In recent studies, we have shown that neurons contain sufficient levels of the microtubule-severing protein termed katanin to completely break down the axonal microtubule array if not somehow attenuated. The presence of tau on axonal microtubules renders them notably less sensitive to katanin, prompting us to posit that microtubule disintegration in tauopathies may result from elevated severing of the microtubules as they lose tau. In support of this hypothesis, we demonstrate here that pathogenic tau mutants that bind less strongly to microtubules than wild-type tau provide correspondingly less protection against katanin-based severing. Using cultured rat hippocampal neurons, we pursued two potential therapies for fortifying axonal microtubules against excess severing by katanin, under conditions of tau depletion. We found that either deacetylating the microtubules via overexpression of HDAC6 or treating the neurons with NAP, a microtubule-interacting neuroprotective peptide, resulted in notable protection of the microtubules against katanin-based loss. In both cases, we found that these treatments also diminished the characteristic increase in axonal branching that normally accompanies tau depletion, an effect that is also known to be directly related to the severing of microtubules. These observations may be useful in developing therapeutic regimes for preserving microtubules against loss in the axons of patients suffering from tauopathies.