Distinctive characteristics of dopamine neuron release mechanisms: Insights into Parkinson's Disease

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, after Alzheimer's disease, and is characterized not only by progressive motor dysfunction but also by a wide array of non-motor symptoms that frequently emerge during the prodromal phase. These early manifestations, including cognitive and neuropsychiatric impairments, autonomic dysfunction, and sleep disturbances, contribute substantially to disease burden and often precede the onset of motor impairments by years. Although degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and α-synuclein (α-syn) pathology define the classical neuropathology of PD, the molecular basis of selective neuronal vulnerability remains incompletely understood. Growing evidence suggests that calcium (Ca^2 +) dysregulation, mitochondrial dysfunction, oxidative stress, and impaired axonal transport converge to produce early synaptic and axonal failure. Importantly, disruptions in dopamine (DA) release, reuptake, and synaptic vesicle (SV) cycling arise well before overt nigrostriatal degeneration and long before clinically detectable DA depletion. These early presynaptic alterations are increasingly recognized as key drivers of motivational, affective, and reward-processing deficits that typify prodromal PD. In this review, we synthesize evidence supporting the hypothesis that axonal and synaptic dysfunction precedes dopaminergic cell body loss and represents a primary site of disease initiation. We focus on the molecular machinery governing presynaptic DA transmission and examine how its disruption contributes to early circuit dysfunction and progressive neurodegeneration. By looking at these early pathophysiological events, we aim to advance the understanding of PD initiation and identify potential avenues for early diagnosis and disease-modifying interventions.