Age-related synaptic vesicle dysfunction as a prodromal target in Parkinson’s disease: Mechanistic insights from alpha-synuclein biology
Year: 2026
Type: article
Abstract: Aging is the principal biological driver of Parkinson’s disease and provides the molecular context in which α-synuclein transitions from a physiological presynaptic organizer to a pathological mediator of synaptic failure. Age-related declines in mitochondrial efficiency, lipid homeostasis, proteostasis, and autophagic flux disrupt synaptic vesicle architecture and function—lowering the threshold for α-synuclein misfolding, membrane dysregulation, and toxic gain-of-function. In this vulnerable presynaptic environment, neurons become functionally compromised long before cell death occurs, creating a prolonged prodromal window in which early therapeutic intervention may be most effective. This narrative review synthesizes mechanistic evidence from human studies, animal models, and in vitro systems, indicating that α-synuclein regulates synaptic vesicle clustering, curvature stabilization, and neurotransmitter release under physiological conditions, but that age-dependent alterations in lipid composition, phosphatidylserine asymmetry, oxidative stress, and autophagy promote its mislocalization and aggregation. These changes generate early presynaptic disturbances—including depletion of synaptophysin and vesicle-associated membrane protein 2, impaired vesicle docking and release probability, and reduced neurotransmission efficiency—that precede dopaminergic degeneration and clinical symptoms. Human biofluid studies demonstrate that vesicle-associated proteins and lipids reflect these early alterations and may serve as accessible biomarkers of impending disease. Current research, however, is limited by the predominant use of young animal models, insufficient mimicry of the aging microenvironment, and a lack of longitudinal approaches capable of resolving dynamic synaptic vesicle changes across the lifespan. The evidence reviewed here supports reframing Parkinson’s disease as an aging-dependent synaptopathy in which presynaptic vulnerability represents the earliest actionable stage of disease. Targeting age-related synaptic vesicle dysfunction and maintaining synaptic homeostasis may offer a pathway toward delaying or preventing the progression from prodromal states to clinically manifest Parkinson’s disease.
Source: Aging advances.
Author: Oscar Arias-Carrión
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7149421572