Bridging Cytoskeletal and Epitranscriptomic Mechanisms: L-DOPA–Induced Microtubule Remodeling Meets m⁶A RNA Methylation in Neural Disorders

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, α-synuclein aggregation, and disrupted motor and non-motor function (Bloem et al., 2021). Pharmacological replenishment of dopamine using L-3,4-dihydroxyphenylalanine (L-Dopa) remains the cornerstone of PD management; however, long-term exposure frequently induces motor fluctuations, dyskinesias, and cognitive side effects (Olanow & Obeso, 2021). Recent mechanistic evidence reveals that L-Dopa itself, independent of its metabolic conversion to dopamine, can be aberrantly incorporated into neuronal microtubules, leading to structural and synaptic instability (Zorgniotti et al., 2025). L-Dopa acts as a tyrosine analogue within the tubulin tyrosination–detyrosination cycle, where tubulin tyrosine ligase (TTL) catalyzes its attachment to α-tubulin. The resulting L-Dopa–modified microtubules resist enzymatic removal by the vasohibin-1/small vasohibin-binding protein (VASH1–SVBP) complex, thereby accumulating in neurons and impairing cytoskeletal plasticity (Peris & Moutin, 2023; Zorgniotti et al., 2025). Functionally, this modification disrupts dendritic spine invasion, reduces excitatory synaptic density, and perturbs intracellular transport, culminating in synaptic weakening and neurofunctional decline. These findings introduce a cytoskeletal dimension to L-Dopa neurotoxicity, linking pharmacotherapy to microtubule dysregulation and altered neuronal connectivity. Understanding the molecular interface between L-Dopa metabolism and tubulin dynamics may inform strategies to mitigate long-term treatment complications and preserve synaptic integrity in PD.