Crosstalk between acetylation and the tyrosination/detyrosination cycle of α-tubulin in Alzheimer's disease.
Crosstalk between acetylation and the tyrosination/detyrosination cycle of α-tubulin in Alzheimer's disease.
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DOI：
10.3389/fcell.2022.926914
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发表时间：
2022
影响因子：
5.5
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中科院分区：
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微管（MT）支持多种神经元功能，如维持细胞结构，运输和突触可塑性。神经元MT是高度异质性的，由于几种微管蛋白同种型和存在多种翻译后修饰，如脱酪氨酸和乙酰化。微管蛋白酪氨酸化/去酪氨酸化循环是维持MT动力学的关键因素，因为酪氨酸化微管蛋白与更具动力学的MT相关，而去酪氨酸化微管蛋白与更长寿命、更稳定的MT相关。微管蛋白再酪氨酸化功能障碍最近与阿尔茨海默病进展相关。然而，微管蛋白乙酰化在阿尔茨海默病中的意义仍然存在争议。在这里，我们证明了微管蛋白乙酰化积累在死后的脑组织从阿尔茨海默氏症患者和人类神经元窝藏阿尔茨海默氏症的家族APP-V717 I突变。我们进一步表明，微管蛋白再酪氨酸，这是有缺陷的阿尔茨海默氏病，可以控制乙酰化微管蛋白在初级神经元的水平无关的调节微管蛋白乙酰化的酶，这表明减少MT动力学与受损的微管蛋白再酪氨酸可能有助于微管蛋白乙酰化的积累，我们检测到阿尔茨海默氏病。
Microtubules (MTs) support a variety of neuronal functions, such as maintenance of cell structure, transport, and synaptic plasticity. Neuronal MTs are highly heterogeneous due to several tubulin isotypes and the presence of multiple post-translational modifications, such as detyrosination and acetylation. The tubulin tyrosination/detyrosination cycle is a key player in the maintenance of MT dynamics, as tyrosinated tubulin is associated with more dynamic MTs, while detyrosinated tubulin is linked to longer lived, more stable MTs. Dysfunction of tubulin re-tyrosination was recently correlated to Alzheimer’s disease progression. The implication of tubulin acetylation in Alzheimer’s disease has, however, remained controversial. Here, we demonstrate that tubulin acetylation accumulates in post-mortem brain tissues from Alzheimer’s disease patients and human neurons harboring the Alzheimer’s familial APP-V717I mutation. We further show that tubulin re-tyrosination, which is defective in Alzheimer’s disease, can control acetylated tubulin in primary neurons irrespective of the levels of the enzymes regulating tubulin acetylation, suggesting that reduced MT dynamics associated with impaired tubulin re-tyrosination might contribute to the accumulation of tubulin acetylation that we detected in Alzheimer’s disease.