Tubulin tyrosination regulates synaptic function and is disrupted in Alzheimer's disease
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:145 |
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| Enthalten in: |
Brain : a journal of neurology - 145(2022), 7 vom: 29. Juli, Seite 2486-2506 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Peris, Leticia [VerfasserIn] |
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| Links: |
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| Themen: |
42HK56048U |
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| Anmerkungen: |
Date Completed 02.08.2022 Date Revised 08.08.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1093/brain/awab436 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM336805578 |
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| 245 | 1 | 0 | |a Tubulin tyrosination regulates synaptic function and is disrupted in Alzheimer's disease |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Alzheimer’s disease | |
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| 700 | 1 | |a Qu, Xiaoyi |e verfasserin |4 aut | |
| 700 | 1 | |a Soleilhac, Jean Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Lanté, Fabien |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Atul |e verfasserin |4 aut | |
| 700 | 1 | |a Pero, Maria Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Martínez-Hernández, José |e verfasserin |4 aut | |
| 700 | 1 | |a Corrao, Charlotte |e verfasserin |4 aut | |
| 700 | 1 | |a Falivelli, Giulia |e verfasserin |4 aut | |
| 700 | 1 | |a Payet, Floriane |e verfasserin |4 aut | |
| 700 | 1 | |a Gory-Fauré, Sylvie |e verfasserin |4 aut | |
| 700 | 1 | |a Bosc, Christophe |e verfasserin |4 aut | |
| 700 | 1 | |a Blanca Ramirez, Marian |e verfasserin |4 aut | |
| 700 | 1 | |a Sproul, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a Brocard, Jacques |e verfasserin |4 aut | |
| 700 | 1 | |a Di Cara, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Delagrange, Philippe |e verfasserin |4 aut | |
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| 700 | 1 | |a Goldberg, Yves |e verfasserin |4 aut | |
| 700 | 1 | |a Moutin, Marie Jo |e verfasserin |4 aut | |
| 700 | 1 | |a Bartolini, Francesca |e verfasserin |4 aut | |
| 700 | 1 | |a Andrieux, Annie |e verfasserin |4 aut | |
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