The Role of Δfosb in the Pathogenesis of Levodopa-Induced Dyskinesia: Mechanisms and Therapeutic Strategies Publisher

Summary: Research shows ΔFosB drives levodopa-induced dyskinesia in Parkinson’s, suggesting new therapies to reduce movement issues. #Parkinsons #Neurology

Zamanian MY^{1, 2} ; Kamran Z³ ; Tavakoli MR⁴ ; Oghenemaro EF⁵ ; Abohassan M⁶ ; Kubaev A⁷ ; Nathiya D⁸ ; Kaur P⁹ ; Zwamel AH^{10, 11, 12} ; Abdulamer RS¹³
Source: Molecular Neurobiology Published:2025

Abstract

Levodopa-induced dyskinesia (LID) represents a significant complication associated with the long-term administration of levodopa (L-DOPA) for the treatment of Parkinson’s disease (PD). This review examines the critical role of ΔFosB, a transcription factor, in the pathogenesis of LID and explores potential therapeutic interventions. ΔFosB accumulates within the striatum in response to chronic dopaminergic stimulation, thereby driving maladaptive changes that culminate in dyskinesia. Its persistent expression modifies gene transcription, influencing neuronal plasticity and contributing to the sustained presence of dyskinetic movements. This study explains how ΔFosB functions at the molecular level, focusing on its connections with dopamine D1 receptors, the cAMP/PKA signaling pathway, and its regulatory effects on downstream targets such as DARPP-32 and GluA1 AMPA receptor subunits. Additionally, it examines how neuronal nitric oxide synthase (nNOS) affects ΔFosB levels and the development of LID. This review also considers the interactions between ΔFosB and other signaling pathways, such as ERK and mTOR, in the context of LID and striatal plasticity. Emerging therapeutic strategies targeting ΔFosB and its associated pathways include pharmacological interventions like ranitidine, 5-hydroxytryptophan, and carnosic acid. Furthermore, this study addresses the role of JunD, another component of the AP-1 transcription factor complex, in the pathogenesis of LID. Understanding the molecular mechanisms by which ΔFosB contributes to LID offers promising avenues for developing novel treatments that could mitigate dyskinesia and improve the quality of life for PD patients undergoing long-term L-DOPA therapy. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.