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.