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

Microtubules support complex neuronal structures, as well as provide the tracks for long distance transport. In the last decade, multiple studies have also revealed that microtubules control central aspects of synaptic architecture and plasticity. We have recently shown that loss of tubulin tyrosine ligase (TTL) and the subsequent disruption of α-tubulin re-tyrosination is a feature of Alzheimer’s disease and a promoter of synapse loss through the inhibition of microtubule entries into dendritic spines. TTL+/- mice have cognitive deficits, altered LTP, and increased levels of detyrosinated and D2 tubulin, two tubulin modifications that accumulate on non-dynamic microtubules. Ectopic expression of TTL was protective in neurons, allowing cells treated with oligomeric amyloid β (oAβ) to maintain normal microtubule entries into spines and to avoid the spine loss typically associated with oAβ exposure. In vitro reduction of TTL was also enough to trigger tau hyperphosphorylation in rodent hippocampal neurons. Overall, our results demonstrate the pleiotropic effects caused by a dysfunctional microtubule cytoskeleton, highlighting a detyrosination/re-tyrosination cycle as key of vulnerability for neurons and a potential trigger for neurodegenerative disease. None