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
Date: vie, 26 jul 2024 a las 18:24
Subject: Seminario/ Conferencia con invitada viernes 02/08
To: listciqui , Mariano Bisbal <
mbisbal@immf.uncor.edu>,
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]
