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Tubulin tyrosination regulates synaptic function and is disrupted in Alzheimer's disease
Leticia Peris1, Julie Parato2,3, Xiaoyi Qu2
1Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France.
Brain : a Journal of Neurology
|February 11, 2022
Summary
The tubulin tyrosination/detyrosination cycle is crucial for neuronal health. Defective tubulin tyrosine ligase (TTL) impairs synaptic plasticity and memory, contributing to Alzheimer's disease pathogenesis.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Microtubules are essential for neuronal structure and function.
- The tubulin tyrosination/detyrosination cycle regulates microtubule dynamics.
- Dysregulation of this cycle is implicated in neurodegenerative diseases.
Purpose of the Study:
- To investigate the role of tubulin tyrosine ligase (TTL) in synaptic plasticity and Alzheimer's disease (AD).
- To determine if TTL deficiency affects neuronal structure and function.
- To assess the impact of the tubulin tyrosination/detyrosination cycle on amyloid-beta peptide toxicity.
Main Methods:
- Analysis of TTL heterozygous mice.
- Assessment of dendritic spine density and synaptic plasticity.
- Examination of TTL expression in human Alzheimer's disease brains.
- Investigation of microtubule dynamics in human neurons with APP mutations.
- Evaluation of synaptic resistance to amyloid-beta peptide toxicity.
Main Results:
- TTL heterozygous mice showed reduced tyrosinated microtubules, dendritic spine density, synaptic plasticity, and memory.
- Decreased TTL expression was observed in sporadic and familial Alzheimer's disease.
- Human neurons with APP mutations exhibited reduced microtubule dynamics.
- Dynamic microtubules protected synapses against amyloid-beta peptide toxicity.
- Restoring TTL expression suppressed amyloid-beta-induced synapse loss.
Conclusions:
- A balanced tubulin tyrosination/detyrosination cycle is vital for synaptic plasticity and neuronal homeostasis.
- Defective tubulin retyrosination contributes to synaptic dysfunction in Alzheimer's disease.
- Targeting the tubulin tyrosination cycle may offer therapeutic strategies for Alzheimer's disease.
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