L-Dopa-modified microtubules lead to synapse instability in cultured neurons: possible implications in Parkinson's disease therapy.

L-Dopa, the main Parkinson's disease treatment, unexpectedly alters the postsynaptic architecture of cultured mouse neurons through its incorporation into α-tubulin via tubulin tyrosine ligase (TTL). This leads to the formation of L-Dopa-modified microtubules, with impaired dynamics and reduced entry into dendritic spines, increasing their vulnerability to pruning. As a result, dendritic spine density-particularly mature spines-and the number of excitatory synapses are significantly reduced. L-Dopa-mediated synaptic defects are absent in neurons lacking the ability to incorporate it into α-tubulin-TTL or SVBP knockout neurons-confirming a microtubule-dependent mechanism. In vitro, L-Dopa-modified tubulin interfered with VASH1-SVBP activity, the major brain's tubulin carboxypeptidase, potentially prolonging L-Dopa-microtubule persistence and turning this therapeutic agent into a driver of long-lasting neuronal changes. These findings reveal a novel mechanism of L-Dopa-induced synaptotoxicity-mediated by the disruption of microtubule dynamics and the tubulin tyrosination/detyrosination cycle-with possible implications for the long-term adverse effects of L-Dopa therapy.