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Page 38 Chakraborty et al. Extracell Vesicles Circ Nucleic Acids 2023;4:27-43 https://dx.doi.org/10.20517/evcna.2023.05

with the diversity of protein and lipid compositions within each of these, call for caution when using these
nomenclatures because of likely molecular overlap, yet considerable (yet unknown) differences in function/
regulation.

Overall, the concomitant role of EVs and TNTs in inflammation and immune response, along with the
overlap we can observe in the molecular actors involved in their formation (IRSp53, CD9/CD81), suggests
the studies of EVs could help us improve our understanding of TNTs and vice versa, by the identification of
common actors and regulators. Determining where their molecular pathways cross and divide represents a
key objective for both the fields of TNTs and EVs.

As discussed above, TNTs are capable of transferring a myriad of intracellular materials from one cell to
2+
another. In physiological contexts, while transfer of Ca can allow electrical coupling and subsequent
development of immature cells, movement of “death signals” can bring about a global senescent response by
the network of connected cells. Similarly, movement of mitochondria can help rescue an apoptotic cell,
while movement of damaged lysosomes containing protein aggregates can spread neurodegenerative
pathologies. Quite recently, mitochondrial movement has been reported to occur from mesenchymal stem
[130]
cells to neurons as a potential protective mechanism in place . Although we focused on the roles of TNTs
in pathological spread of toxic protein aggregates, the influence of secretion in disease spread is significant.
Several protein aggregates are released by cells that can be taken up by neighboring cells, or accumulate
extracellularly. It is highly plausible that there exists a concerted mechanism (yet unknown) of secretion-
and TNT-based intercellular communication that takes place in symbiosis to cause ND spread. Our limited
understanding of TNTs in vivo also poses a challenge in understanding not only ND progression across
different Braak stages , but also in testing the potential interplay of secreted vesicles and TNTs in disease
[101]
progression. Future studies would require assessing the presence of TNTs in healthy and diseased brains,
with stringent emphasis on characterization of the structures as TNTs or TNT-like.

As such, TNTs have been rightly referred to as a “double-edged sword” that can be both beneficial and
detrimental, depending on the context of formation. This raises important questions about to what extent is
the movement of context-specific molecules between healthy and unhealthy cells actively regulated, and
what are the molecular players involved in “sensing” which material(s) to transfer.

DECLARATIONS
Acknowledgements
The authors would like to thank Reine Bouyssie, a member of the administrative staff of the Membrane
Traffic and Pathogenesis Unit at Institut Pasteur, for her continued support.

Author’s Contributions
Conceived the idea for the manuscript: Zurzolo C
Wrote, revised and edited the manuscript: Chakraborty R., Belian S. and Zurzolo C
Prepared Figure 1: Belian S
Prepared Figures 2, 3, and Table 1: Chakraborty R

Availability of Data and Materials
Not applicable.

Financial Support and Sponsorship
Chakraborty, R. is supported by the Pasteur-Paris University international doctoral program. Belian, S.
acknowledges PhD funding support from ANR (ANR-20-CE13-0032-01). This work was supported by