Year: 2025
Type: article
Abstract: Neurotransmitter release occurs through exocytosis of synaptic vesicles. α-Synuclein's function and dysfunction in Parkinson's disease and other synucleinopathies is thought to be tightly linked to synaptic vesicle binding. Age is the biggest risk factor for synucleinopathy, and ~15% of synaptic vesicle proteins have been linked to central nervous system diseases. Yet, age- and disease-induced changes in synaptic vesicles remain unexplored. Via systematic analysis of synaptic vesicles at the ultrastructural, protein, and lipid levels, we reveal specific changes in synaptic vesicle populations, proteins, and lipids over age in wild-type mice and in α-synuclein knockout mice with and without expression of human α-synuclein. Strikingly, we find several previously undescribed synaptic changes in mice lacking α-synuclein, suggesting that loss of α-synuclein function contributes to synaptic dysfunction. These findings not only provide insights into synaptic vesicle biology and disease mechanisms in synucleinopathy, but also serve as a baseline for further mechanistic exploration of age- and disease-related alterations in synaptic vesicles.
Source: Nature Communications
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Howard Hughes Medical Institute, U.S. Department of Health and Human Services, Yale University, Parkinson's Foundation, National Institutes of Health, University of California, San Diego, National Institute on Aging, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Yale Liver Center, Common Fund
Awards: G174479158, The role of beta-synuclein in synaptic vesicle release, G2075703296, G254309129, G3111867497, G3147758498, Circuit-specific, chemogenetic neuromodulation in nonhuman primates., G339728923, G3645388351, The impact of synaptic vesicle-binding of alpha-synuclein on neuron function and neuropathology, G384225692, G4006362367, Cellular mechanism of Adult Onset Neuronal Ceroid Lipofuscinosis (ANCL) caused by mutations in cysteine string protein-alpha (CSPalpha)., Synaptic vesicle changes in synucleinopathies, G466983291, G4878779844, G4977806179, Biomedical Data Commons Workbench (BDCW), G5182919324, G526553736, G5948757532, A multiplexable in vivo perturbation toolkit to identify genes affecting neurodegeneration in a model of synucleinopathy, G6667022208, Advancing Success and Persistence in Research Education (ASPiRE), G7541701349, G764885983, G7869094047, G8415654023, G849215759, G9000048486, The role of VAMP2 in alpha-synuclein function and pathology, The Impact of Beta- and Gamma-Synucleins on Alpha-Synuclein's Synaptic Function
OpenAlex ID: W4410010979