Current therapeutic strategies in Parkinson's disease: Future perspectives

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation of misfolded α-synuclein. Current treatments, including dopaminergic medications and deep brain stimulation, provide symptomatic relief but do not halt disease progression. Recent advances in molecular research have enabled the development of disease-modifying strategies targeting key pathogenic mechanisms, such as α-synuclein aggregation, mitochondrial dysfunction, and genetic mutations, including LRRK2 and GBA1. In parallel, pluripotent stem cell-derived dopaminergic neurons have emerged as a scalable and ethically viable source for cell replacement therapy. Early-phase clinical trials have demonstrated the safety and functional integration of these grafts. Ongoing research is now focused on enhancing graft purity, immune compatibility, and anatomical precision, including homotopic transplantation and circuit-level reconstruction. Together, these emerging strategies offer the potential to shift PD treatment paradigms by combining symptomatic control with long-term neural restoration. This review summarizes current therapeutic approaches and highlights recent advances in disease-modifying and regenerative interventions for PD.

Keywords: Cell replacement therapy; Dopaminergic neurons; Neurodegeneration; Parkinson's disease; Pluripotent stem cell.

Fig. 1

Dopaminergic regulation of the basal ganglia motor circuit and therapeutic strategies for Parkinson’s disease (PD). (A) Basal ganglia circuitry under normal conditions. The basal ganglia control movement through direct and indirect pathways originating from the striatum. Dopamine from the substantia nigra pars compacta (SNpc) modulates these pathways by activating D1 receptors (direct pathway, promoting movement) and D2 receptors (indirect pathway, suppressing movement). The globus pallidus internus (GPi) exerts tonic inhibition on the thalamus, which regulates motor cortex activity. Dopaminergic modulation ensures proper movement initiation and suppression. (B) Circuit dysfunction in PD. Loss of SNpc neurons reduces striatal dopamine, weakening the direct pathway and overactivating the indirect pathway. This enhances GPi-mediated thalamic inhibition, resulting in motor symptoms such as bradykinesia and rigidity. Deep brain stimulation (DBS) of the STN or GPi helps restore balance by suppressing pathological overactivity. (C) Dopamine restoration therapies. L-Dopa and striatal cell transplantation aim to restore dopamine levels and re-establish functional output of basal ganglia circuits. (D) Intranigral grafting for circuit reconstruction. Transplanting dopaminergic neurons into the SN may enable reformation of the nigrostriatal pathway, restoring more physiological connectivity. While effective in rodents, the longer axonal distances in humans present a challenge. Adjunctive approaches using neurotrophic factors, axon guidance molecules, or biomaterials may support long-distance axonal growth and integration in clinical settings. GDNF, glial cell line-derived neurotrophic factor; GPe, globus pallidus externus. Created in BioRender (https://BioRender.com/rhaheq1).