New insights into synaptic vesicle dysfunction in Parkinson's disease.

Parkinson's disease (PD) is characterized by progressive motor and non-motor dysfunction arising from synaptic pathology that precedes neuronal loss. Synaptic dysfunction represents a central pathological mechanism in both familial and sporadic PD, with multiple PD-linked genes directly regulating synaptic vesicle (SV) trafficking. Here, we review recent studies linking SV dysfunction to PD pathology by examining how disease-linked proteins dysregulate distinct steps in the SV cycle and by exploring their cascading effects on synaptic physiology and circuit function. We highlight three critical pathogenic mechanisms: (1) impaired neurotransmitter import and storage, (2) disrupted SV pool organization, and (3) altered SV exocytosis and endocytosis. We also review recent studies investigating how presynaptic pathology triggers impairments in postsynaptic plasticity and circuit-level reorganization across brain regions. Together, these studies highlight that presynaptic SV dysfunction is a central mechanism in PD pathogenesis and therefore a promising target for developing therapeutic strategies aimed at reverting these early disease-driving synaptic changes.

VIVO Weill Cornell Medical College