Estimados/as, Iniciando el ciclo de conferencias por el 42 aniversario del CIQUIBIC, les invitamos a la presentación que nos brindará la Dra. Leticia Peris, investigadora del GIN (Grenoble Institut Neurosciences, de la Université Grenoble Alpes, Francia), el próximo *viernes 02/08 a las 13,30h *en la nueva sala "Aula H". Titulo: *L-Dopa incorporation into tubulin alters microtubule dynamics and reduces dendritic spine invasion and synapse maintenance* Resumen: *Previous research has indicated that L-Dopa, a tyrosine analog used in Parkinson's disease treatment, can be incorporated into the C-terminal tail of α-tubulin via tubulin tyrosine ligase (TTL) and subsequently polymerize into microtubules. In this study, we demonstrated that mature wild-type hippocampal neurons treated with L-Dopa exhibited reduced dendritic spine density, particularly affecting mature dendritic spines. L-Dopa treatment also decreased the percentage of excitatory synapses in the remaining spines of wild-type neurons, suggesting a cumulative synaptic defect affecting the quantity and quality of the synapses. L-Dopa treatment of these neurons significantly decreased α-tubulin tyrosination levels in proportion to the emergence of a new tubulin pool, likely formed by L-Dopa-α-tubulin.* *In vitro analysis of the purified VASH1-SVBP complex, the most abundant tubulin carboxypeptidase in the brain, revealed that the presence of L-Dopa-tubulin alters the complex's binding to microtubules and reduces its carboxypeptidase activity. These findings suggest that L-Dopa incorporation into tubulin modifies microtubule properties and their interaction with this enzyme.* *To confirm the involvement of L-Dopa-microtubules in the observed dendritic spine alterations in wild-type neurons, we examined the effect of L-Dopa treatment also affect neurons lacking the enzymes of the α-tubulin detyrosination/tyrosination cycle. In these neurons, L-Dopa cannot be incorporated into α-tubulin due to the absence of the ligase (in TTL knockout neurons) or reduced levels of the substrate: detyrosinated α-tubulin (in SVBP knockout neurons). L-Dopa treatment did not alter dendritic spine density or excitatory synapses in TTL KO or SVBP KO neurons, clearly indicating that the post-synaptic defects observed in WT neurons are due to L-Dopa incorporation into tubulin. Further analysis revealed that in WT neurons, L-Dopa altered microtubule dynamics in the dendritic shaft by increasing catastrophe frequency and reducing comet lifetime, resulting in fewer microtubules entering dendritic spines and decreased spine resistance to pruning.* *In summary, our findings show that L-Dopa incorporation into α-tubulin dramatically disrupts synaptic homeostasis, underscoring the crucial role of balanced tyrosination/detyrosination of tubulin in the synaptic compartment. The abnormal dynamic of L-Dopa-modified microtubules, along with the reduction in dendritic spines and excitatory synapses, reveal a novel mechanism of L-Dopa-induced synaptotoxicity. This is particularly pertinent in the chronic treatment of Parkinson's disease, highlighting the necessity for new therapeutic strategies that mitigates these synaptic side effects.* Les esperamos. [image: Seminario LPeris.png]
