Synaptic vesicle-omics in mice captures signatures of aging and synucleinopathy
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.
Authors
- Jacqueline Burré (ORCID: https://orcid.org/0000-0001-8968-248X)
- André Pineda (ORCID: https://orcid.org/0000-0002-9263-3299)
- Diane Lane (ORCID: https://orcid.org/0000-0001-7313-557X)
- Manu Sharma (ORCID: https://orcid.org/0000-0001-7394-2419)
- Juan Antonio Briano (ORCID: https://orcid.org/0000-0003-0745-9415)
- Lauren E. Komer (ORCID: https://orcid.org/0000-0002-6114-8637)
- Serge Przedborski (ORCID: https://orcid.org/0000-0002-7283-3883)
- Julita Chlebowicz (ORCID: https://orcid.org/0000-0002-0437-0338)
- Kerry Gaskin (ORCID: https://orcid.org/0000-0002-1179-4921)
- Virginia Gao (ORCID: https://orcid.org/0000-0002-5595-1175)
- Sheng Zhang (ORCID: https://orcid.org/0000-0001-8206-1007)
- Saad Ahmad (ORCID: https://orcid.org/0009-0008-1367-3059)
- Jillian E. Haller
- Luca S Black
- Shrey Jhalani
- Eseosa Uwaifo
Institutions
- University of Notre Dame (US)
- Cornell University (US)
- Columbia University Irving Medical Center (US)
- MIND Research Institute (US)
- Columbia University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1038/s41467-025-59441-7
- Citations
- 6
- Primary Topic
- Cellular transport and secretion
- Type
- article
- Field-Weighted Citation Impact
- 6.91
Funders
- Howard Hughes Medical Institute
- 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 Neurological Disorders and Stroke
- Yale Liver Center
- Common Fund