Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes
Open accessAbstract
Synucleinopathies such as Parkinson's disease are characterized by the pathological deposition of misfolded α-synuclein aggregates into inclusions throughout the central and peripheral nervous system. Mounting evidence suggests that intercellular propagation of α-synuclein aggregates may contribute to the neuropathology; however, the mechanism by which spread occurs is not fully understood. By using quantitative fluorescence microscopy with co-cultured neurons, here we show that α-synuclein fibrils efficiently transfer from donor to acceptor cells through tunneling nanotubes (TNTs) inside lysosomal vesicles. Following transfer through TNTs, α-synuclein fibrils are able to seed soluble α-synuclein aggregation in the cytosol of acceptor cells. We propose that donor cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. Our findings thus reveal a possible novel role of TNTs and lysosomes in the progression of synucleinopathies.
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α-synuclein fibrils damage lysosomes and propagate between neurons via lysosome-associated cargo transported through tunneling nanotubes.
“Concurrently, α-syn fibrils damage lysosomes and propagate between neurons via lysosome-associated cargo transported through TNTs, providing a TNT-dependent route for pathology spread [151,152].”
From The Impact of Neurotoxin Proteins Trafficked by Primary Cilia and Extracellular Vesicles in Neurodegenerative Diseases (2025) · cites this paper as [151]
The Abstract reports that α-synuclein fibrils move between co-cultured neurons through TNTs inside lysosomal vesicles. The Discussion reports enlarged lysosomes but presents fibril-induced lysosomal impairment as a hypothesis, not a demonstrated finding. Page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredαSyn has the ability to spread via direct neuron-to-neuron transfer.
“iii) αSyn has the ability to spread to adjacent cells via secretion in exosomes [209], uptake via endocytosis [210] and cell-surface receptors like HSPGs, or even direct neuron-to-neuron [211, 212] or astrocyte-to-neuron [213] transfer via tunneling nanotubes (Fig. 2).”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [211]
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“Concurrently, α -syn fibrils damage lysosomes and propagate between neurons via lysosome-associated cargo transported through TNTs, providing a TNT-dependent route for pathology spread [151,152].”
- Authors
- Abounit, S., Bousset, L., Loria, F., Zhu, S., de Chaumont, F., Pieri, L., Olivo‐Marin, J., Melki, R., & Zurzolo, C.
- Affiliations
- Institut Pasteur (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Zurzolo, Chiara
- Venue
- The EMBO Journal
- Published
- 2016-08-22
- Volume
- 35
- Issue
- 19
- Pages
- 2120-2138
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC5048354
- OpenAlex
- W2512060277
- Cited by
- 414
- References
- 72
- Citations by year
- 2026: 28 · 2025: 28 · 2024: 54 · 2023: 34 · 2022: 44 · 2021: 44 · 2020: 55 · 2019: 40 · 2018: 45 · 2017: 32 · 2016: 9
- FWCI
- 31.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Ministère de l'Education Nationale
- Fondation Bettencourt‐Schueller
- Fondation pour la Recherche Médicale (FDT20140931208, DEQ20140329557)
- Marie Skłodowska‐Curie Fellowship
- China Scholarship Council
- MI CARNOT ICSA/PMI
- Agence Nationale de la Recherche (ANR‐14‐JPCD‐0002‐01)
- Fondation de France (2015‐00060936)
- Centre National de la Recherche Scientifique
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- tunneling nanotubes, alpha-synuclein, lysosomes, intercellular trafficking, synucleinopathies, Parkinson's disease, lysosomal escape, neurons
- MeSH terms
- Amyloid, Animals, Cell Communication, Cells, Cultured, Lysosomes, Microscopy, Fluorescence, Neurons, Coculture Techniques, Nanotubes, Mice, alpha-Synuclein
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