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

Abstract

Sonu Kumar*

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, α-synuclein aggregation, and disrupted motor and non-motor function [1]. 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 [2]. 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 [3]. L-DOPA acts as a tyrosine analogue within the tubulin tyrosination–de–tyrosination cycle, where tubulin tyrosine ligase (TTL) catalyses 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 [3,4]. 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.

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