Estimados,
recuerden que este viernes tendremos la presentación de la Dra. Peris, a las 13,30h en el aula H.
Les esperamos
Comisión de Seminarios

---------- Forwarded message ---------
De: Mauricio Galiano <mauricio.galiano@unc.edu.ar>
Date: vie, 26 jul 2024 a las 18:24
Subject: Seminario/ Conferencia con invitada viernes 02/08
To: listciqui <Listciqui@fcq.unc.edu.ar>, Mariano Bisbal <mbisbal@immf.uncor.edu>, <analismoyano@gmail.com>


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.
Seminario LPeris.png