Autophagy is a fundamental cellular process that plays a role in many physiological and pathophysiological processes. Microtubules are dynamic cytoskeletal fibers composed of tubulin dimers that have diverse structure and functions in cells. They are notably involved in cellular trafficking and autophagosome formation. The detyrosination/tyrosination cycle, a post-translational modification of tubulin, controls microtubule functions in healthy neurons, and its dysregulations lead to neuronal defects. This cycle is characterized by the enzymatic removal and re-addition of a gene-encoded tyrosine residue at the C-terminus of α-tubulin by the tubulin tyrosine ligase (TTL) and three detyrosinases, the vasohibin (VASH1 or VASH2) -small vasohibin-binding protein (SVBP) complexes, and MATCAP respectively. Our recent data indicate elevated detyrosinated α-tubulin levels in the brain of Alzheimer’s disease patients. This defect is relevant because microtubules are important for autophagy, which is defective in neurodegeneration and could accelerate disease progression via toxic aggregate accumulation. We hypothesize that neuron malfunction associated with proteotoxicity is, at least in part, related to excessive detyrosination. We are thus currently investigating the interplay between microtubule (de)tyrosination and autophagy in the brain and neurons. We use neurons and tissues from mice of different genotypes with altered tubulin (de)tyrosination which we have recently developed. Our preliminary results show that reducing detyrosination (SVBP loss) increases autophagic flux in cultured cortical neurons, whereas reducing the tyrosination (TTL loss) seems to have an opposite tendency. Moreover, basal autophagy increases in cerebral cortices of SVBP-KO mice compared to wildtype mice. Thus, microtubule tyrosination status seems to influence neuronal autophagy.