Synaptic vesicle-omics in mice captures signatures of aging and synucleinopathy

Virginia Gao, Julita Chlebowicz, Karlton Gaskin, Juan A. Briano, Lauren E. Komer, André Pineda, Shrey Jhalani, Saad Ahmad, Eseosa Uwaifo, Luca S. Black, Jillian E. Haller, Serge Przedborski, Diane A. Lane, Sheng Zhang, Manu Sharma and Jacqueline Burré ()
Additional contact information
Virginia Gao: Weill Cornell Medicine
Julita Chlebowicz: Weill Cornell Medicine
Karlton Gaskin: Weill Cornell Medicine
Juan A. Briano: Weill Cornell Medicine
Lauren E. Komer: Weill Cornell Medicine
André Pineda: Weill Cornell Medicine
Shrey Jhalani: Weill Cornell Medicine
Saad Ahmad: Weill Cornell Medicine
Eseosa Uwaifo: Weill Cornell Medicine
Luca S. Black: Weill Cornell Medicine
Jillian E. Haller: Weill Cornell Medicine
Serge Przedborski: Columbia University
Diane A. Lane: Weill Cornell Medicine
Sheng Zhang: Cornell University
Manu Sharma: Weill Cornell Medicine
Jacqueline Burré: Weill Cornell Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59441-7

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