Impaired α-tubulin re-tyrosination leads to synaptic dysfunction and is a feature of Alzheimer’s disease

Leticia Peris (1) , Xiaoyi Qu (2) , Jean-Marc Soleilhac (1) , Julie Parato (2) , Fabien Lanté (1) , Atul Kumar (2) , Maria Elena Pero (2, 3) , José Martínez-Hernández (1) , Charlotte Corrao (1) , Giulia Falivelli (1) , Floriane Payet (1) , Sylvie Gory-Fauré (1) , Christophe Bosc (1) , Marian Blanca Ramírez (2) , Andrew Sproul (2) , Jacques Brocard (1) , Benjamin Di Cara (4) , Philippe Delagrange (4) , Alain Buisson (1) , Yves Goldberg (1) , Marie-Jo Moutin (1) , Francesca Bartolini (2) , Annie Andrieux (1)

1 GIN - [GIN] Grenoble Institut des Neurosciences
2 CUMC - Columbia University Medical Center
3 University of Naples Federico II = Università degli studi di Napoli Federico II
4 IRS - Institut de Recherches SERVIER

SUMMARY In neurons, dynamic microtubules play regulatory roles in neurotransmission and synaptic plasticity. While stable microtubules contain detyrosinated tubulin, dynamic microtubules are composed of tyrosinated tubulin, suggesting that the tubulin tyrosination/detyrosination (Tyr/deTyr) cycle modulates microtubule dynamics and synaptic function. In the Tyr/deTyr cycle, the C-terminal tyrosine of α-tubulin is re-added by tubulin-tyrosine-ligase (TTL). Here we show that TTL +/− mice exhibit decreased tyrosinated microtubules, synaptic plasticity and memory deficits, and that reduced TTL expression is a feature of sporadic and familial Alzheimer’s disease (AD), with human APPV717I neurons having less dynamic microtubules. We find that spines visited by dynamic microtubules are more resistant to Amyloidβ 1-42 and that TTL, by promoting microtubule entry into spines, prevents Aβ 1-42 -induced spine pruning. Our results demonstrate that the Tyr/deTyr cycle regulates synaptic plasticity, is protective against spine injury, and that tubulin re-tyrosination is lost in AD, providing evidence that a defective Tyr/deTyr cycle may contribute to neurodegeneration.

Domaines: Sciences du Vivant [q-bio]

Leticia Peris, Xiaoyi Qu, Jean-Marc Soleilhac, Julie Parato, Fabien Lanté, et al.. Impaired α-tubulin re-tyrosination leads to synaptic dysfunction and is a feature of Alzheimer’s disease. 2021. ⟨hal-03432440⟩