Tubulin tyrosination regulates synaptic function and is disrupted in Alzheimer's disease.
Tubulin tyrosination regulates synaptic function and is disrupted in Alzheimer's disease.
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DOI：
10.1093/brain/awab436
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发表时间：
2022-07-29
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影响因子：
--
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微管在维持神经元突起、突触功能和可塑性方面发挥着重要作用。动态微管主要由酪氨酸化的微管组成，而长寿命的微管含有变性的微管蛋白，这表明微管蛋白酪氨酸化/变性循环在维持微管动力学和神经元动态平衡方面起着关键作用，而这正是神经退行性疾病中出错的条件。在酪氨酸化/去酪氨酸化循环中，微管蛋白的C端酪氨酸被微管蛋白羧肽酶去除，再被微管蛋白酪氨酸连接酶重新加入。α-微管蛋白的C-末端酪氨酸被微管蛋白羧肽酶去除，再被微管蛋白酪氨酸连接酶重新加入。在这里，我们显示TTL杂合子小鼠表现出酪氨酸化微管减少，树突棘密度减少，突触可塑性和记忆缺陷。我们进一步报告了散发性和家族性阿尔茨海默病患者TTL表达的降低，以及携带家族性APP-V717I突变的人类神经元中微管动力学的降低。最后，我们发现被动态微管访问的突触对寡聚淀粉样蛋白β多肽的毒性具有更强的抵抗力，并且TTL1的表达通过恢复微管进入脊髓来抑制由淀粉样蛋白β多肽诱导的突触丢失。综上所述，我们的结果表明，平衡的酪氨酸化/酪氨酸化微管蛋白循环对于维持突触的可塑性是必要的，对于淀粉样蛋白-β肽诱导的突触损伤具有保护作用，并且这种平衡在阿尔茨海默病中被破坏，提供了证据表明微管蛋白酪氨酸化缺陷可能导致阿尔茨海默病神经退行性变过程中的电路功能障碍。Peris，Parato，Qu等人。证明微管蛋白酪氨酸连接酶(TTL)在阿尔茨海默病中减少，TTL半合子小鼠表现出记忆障碍和突触完整性降低。微管蛋白反转通过促进微管进入树突棘来保护β诱导的突触损伤。
Microtubules play fundamental roles in the maintenance of neuronal processes and in synaptic function and plasticity. While dynamic microtubules are mainly composed of tyrosinated tubulin, long-lived microtubules contain detyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination cycle is a key player in the maintenance of microtubule dynamics and neuronal homeostasis, conditions that go awry in neurodegenerative diseases. In the tyrosination/detyrosination cycle, the C-terminal tyrosine of α-tubulin is removed by tubulin carboxypeptidases and re-added by tubulin tyrosine ligase (TTL). Here we show that TTL heterozygous mice exhibit decreased tyrosinated microtubules, reduced dendritic spine density and both synaptic plasticity and memory deficits. We further report decreased TTL expression in sporadic and familial Alzheimer’s disease, and reduced microtubule dynamics in human neurons harbouring the familial APP-V717I mutation. Finally, we show that synapses visited by dynamic microtubules are more resistant to oligomeric amyloid-β peptide toxicity and that expression of TTL, by restoring microtubule entry into spines, suppresses the loss of synapses induced by amyloid-β peptide. Together, our results demonstrate that a balanced tyrosination/detyrosination tubulin cycle is necessary for the maintenance of synaptic plasticity, is protective against amyloid-β peptide-induced synaptic damage and that this balance is lost in Alzheimer’s disease, providing evidence that defective tubulin retyrosination may contribute to circuit dysfunction during neurodegeneration in Alzheimer’s disease. Peris, Parato, Qu et al. demonstrate that tubulin tyrosine ligase (TTL) is reduced in Alzheimer’s disease and that TTL hemizygous mice show memory impairment and reduced synaptic integrity. Tubulin retyrosination by TTL protects against Aβ-induced synaptic damage by promoting microtubule entry into dendritic spines.
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DOI：
10.1016/s0140-6736(20)32205-4
发表时间：
2021-04-24
期刊：
Lancet (London, England)
影响因子：
--
作者：
Scheltens P;De Strooper B;Kivipelto M;Holstege H;Chételat G;Teunissen CE;Cummings J;van der Flier WM
通讯作者：
van der Flier WM
DOI：
10.1083/jcb.104.4.1059
发表时间：
1987-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Wehland J;Weber K
通讯作者：
Weber K
影响因子：
56.9
作者：
Aillaud, Chrystelle;Bosc, Christophe;Moutin, Marie-Jo
通讯作者：
Moutin, Marie-Jo
影响因子：
--
作者：
Cheng, Chialin;Fass, Daniel M;Haggarty, Stephen J
通讯作者：
Haggarty, Stephen J
影响因子：
5.3
作者：
Hu, Xindao;Viesselmann, Chris;Dent, Erik W.
通讯作者：
Dent, Erik W.