Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms.
Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms.
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DOI：
10.3389/fnins.2017.00572
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发表时间：
2017
影响因子：
4.3
通讯作者：
Kanaan NM
中科院分区：
文献类型：
--
作者：
Kneynsberg A;Combs B;Christensen K;Morfini G;Kanaan NM
Tauopathy是一组不同的疾病，其特征是特定神经元群体的进行性退行性神经变性，并伴随着异常形式的微管相关蛋白tau的积累。众所周知，肌萎缩侧索硬化症的临床症状与病程早期突触功能和神经连接的缺陷有关，但这些关键致病事件背后的机制尚未完全清楚。体外生化证据支持了一种广泛的观点，即微管稳定代表了tau的主要生物学作用，并认为tau病中观察到的明显的神经突起萎缩是微管稳定性丧失的结果。然而，这一概念与tau缺失相关的轻微表型形成了鲜明对比。相反，对不同tau病共同的细胞特征的分析，包括蛋白磷酸化的异常模式和轴突的早期退化，表明基于激酶的信号通路的改变和与此相关的轴突运输(AT)缺陷导致由tau的致病形式引发的神经元连接的丧失。在这里，我们回顾了大量文献提供的证据，证明轴突病理是人类脊椎病中的一种早期和常见的致病事件。观察到轴突变性在动物模型中的具体转归进行了讨论，并强调了与人类疾病的相似性。最后，我们讨论了微管失稳以外的潜在机制途径，疾病相关形式的tau可能通过这些途径促进轴索病变。
Tauopathies are a diverse group of diseases featuring progressive dying-back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated protein tau. It is well-established that the clinical symptoms characteristic of tauopathies correlate with deficits in synaptic function and neuritic connectivity early in the course of disease, but mechanisms underlying these critical pathogenic events are not fully understood. Biochemical in vitro evidence fueled the widespread notion that microtubule stabilization represents tau's primary biological role and that the marked atrophy of neurites observed in tauopathies results from loss of microtubule stability. However, this notion contrasts with the mild phenotype associated with tau deletion. Instead, an analysis of cellular hallmarks common to different tauopathies, including aberrant patterns of protein phosphorylation and early degeneration of axons, suggests that alterations in kinase-based signaling pathways and deficits in axonal transport (AT) associated with such alterations contribute to the loss of neuronal connectivity triggered by pathogenic forms of tau. Here, we review a body of literature providing evidence that axonal pathology represents an early and common pathogenic event among human tauopathies. Observations of axonal degeneration in animal models of specific tauopathies are discussed and similarities to human disease highlighted. Finally, we discuss potential mechanistic pathways other than microtubule destabilization by which disease-related forms of tau may promote axonopathy.
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影响因子：
6.1
作者：
Brady ST;Morfini GA
通讯作者：
Morfini GA
影响因子：
6.1
作者：
Combs B;Hamel C;Kanaan NM
通讯作者：
Kanaan NM
影响因子：
12.4
作者：
Caillierez, Raphaelle;Begard, Severine;Colin, Morvane
通讯作者：
Colin, Morvane
影响因子：
81.5
作者：
Blennow, Kaj;Brody, David L.;Zetterberg, Henrik
通讯作者：
Zetterberg, Henrik
DOI：
10.1073/pnas.1409952112
发表时间：
2015-04-21
影响因子：
11.1
作者：
Barrio, Jorge R.;Small, Gary W.;Kepe, Vladimir
通讯作者：
Kepe, Vladimir