Unraveling Parkinson’s disease: from dopaminergic dysfunction to novel therapeutic targets

Parkinson’s disease (PD) is a neurodegenerative disorder influenced by multiple factors and primarily defined by the gradual loss of dopaminergic neurons within the substantia nigra pars compacta. This pathological process fundamentally reduces available dopamine levels and produces core motor symptoms that include bradykinesia, resting tremor, rigidity, postural instability, and a generalized loss of balance. However, the pathology of PD appears to include far more than nigrostriatal function, as it is increasingly recognized that PD extends across the central and peripheral nervous systems through many different neurotransmitter systems/neurotransmitters, neuroinflammation, mitochondrial dysfunction, genetic mutations, abnormal protein aggregation (particularly of α-synuclein), and other factors. Thus, the complexities of PD are suggestive of more of a syndromic process rather than a single disease process with varied pathogenetic pathways that also result in varied clinical presentations. Traditionally, treatment options for PD have primarily focused on dopaminergic treatment strategies to manage the progressive symptoms, which include the lifestyle impact of diminished dopamine levels. This regimen primarily includes levodopa in addition to dopamine agonist options and an array of adjunctive therapies. While these early treatments are completely life-altering and provide considerable improvement for the first several years, their benefit eventually wanes, and they fundamentally simply do not alter disease progression. Recently, there has been a concerted effort to identify treatment options that are not simply a dopaminergic replacement treatment but can alter some aspects of the disease, including several novel approaches investigating mitochondrial health, neuroinflammation, autophagy, α-synuclein aggregation, and genetic regulation in both preclinical and early clinical studies. This review takes a critical look at the classic view of PD occurring as a result of dopaminergic dysfunction, extends into modern concepts that include abnormalities at the cellular and molecular levels, and describes new treatment strategies that fundamentally reflect the multifactorial nature of PD. However, its central aim is to direct the audience to interventions that not only relieve symptoms but also hold the promise to stop or reverse the disease, ultimately offering renewed hope to patients and physicians alike.