Neurotransmitter Dysregulation in Parkinson's Disease: Pathophysiological Insights and Therapeutic Perspectives

Parkinson's disease (PD) is a prevalent neurodegenerative movement disorder characterized by bradykinesia, rigidity, and resting tremor, progressing insidiously over time. Central to its pathophysiology is the degeneration of dopaminergic neurons in the substantia nigra, leading to a significant decrease in striatal dopamine (DA) levels. This dopaminergic deficit disrupts basal ganglia circuitry, impairing motor function and contributing to the core symptoms of the disease. While the etiology of PD remains incompletely understood, a combination of genetic predispositions and environmental exposures has been implicated. Beyond dopaminergic dysfunction, emerging evidence suggests that other neurotransmitter systems, including noradrenergic, serotonergic, cholinergic, glutamatergic, and γ-aminobutyric acidergic (GABAergic) pathways, are also involved in disease progression and symptom heterogeneity. Pathological hallmarks such as α-synuclein (α-syn) misfolding and Lewy body (LB) formation, along with mitochondrial dysfunction, oxidative stress, and neuroinflammation, further exacerbate neurodegeneration and neurotransmitter imbalances. Despite advances in symptomatic treatment, current therapies primarily target DA deficiency and fail to reverse neurodegenerative processes. The involvement of multiple neurotransmitter systems highlights the complex neurochemical landscape of PD and underscores the need for multifaceted therapeutic strategies. Understanding the broader role of neurotransmitters in PD pathogenesis offers promising avenues for disease-modifying interventions and improved symptom management. This review summarizes the recent findings on the contribution of various neurotransmitters to PD, emphasizing their potential as targets for future therapeutic development. By integrating the current literature, we aim to provide a comprehensive overview of neurotransmitter involvement in PD and its implications for advancing treatment paradigms.