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Chakraborty et al. Extracell Vesicles Circ Nucleic Acids 2023;4:27-43 Extracellular Vesicles and
DOI: 10.20517/evcna.2023.05
Circulating Nucleic Acids

Review Open Access

Hijacking intercellular trafficking for the spread of
protein aggregates in neurodegenerative diseases: a

focus on tunneling nanotubes (TNTs)

Ranabir Chakraborty 1,2,# , Sevan Belian 1,2,# , Chiara Zurzolo 1,3
1
Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Membrane Traffic and Pathogenesis, Paris F-75015, France.
2
Université Paris Saclay, Gif-sur-Yvette, Paris 91190, France.
3
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy.
#
Authors contributed equally.
Correspondence to: Chiara Zurzolo, M.D., PhD., Biologie cellulaire et infection, Institut Pasteur, Université Paris Cité, 25-28 Rue
du Docteur Roux Institut Pasteur, Paris F-75015, France. E-mail: chiara.zurzolo@pasteur.fr
How to cite this article: Chakraborty R, Belian S, Zurzolo C. Hijacking intercellular trafficking for the spread of protein aggregates
in neurodegenerative diseases: a focus on tunneling nanotubes (TNTs). Extracell Vesicles Circ Nucleic Acids 2023;4:27-43.
https://dx.doi.org/10.20517/evcna.2023.05

Received: 16 Jan 2023 First Decision: 16 Feb 2023 Revised: 24 Feb 2023 Accepted: 3 Mar 2023 Published: 9 Mar 2023

Academic Editors: Yoke Peng Loh Copy Editor: Ying Han Production Editor: Ying Han

Abstract
Over the years, the influence of secretory mechanisms on intercellular communication has been extensively
studied. In the central nervous system (CNS), both trans-synaptic (neurotransmitter-based) and long-distance
(extracellular vesicles-based) communications regulate activities and homeostasis. In less than a couple of
decades, however, there has been a major paradigm shift in our understanding of intercellular communication.
Increasing evidence suggests that besides secretory mechanisms (via extracellular vesicles), several cells are
capable of establishing long-distance communication routes referred to as Tunneling Nanotubes (TNTs). TNTs are
membranous bridges classically supported by F-Actin filaments, allowing for the exchange of different types of
intracellular components between the connected cells, ranging from ions and organelles to pathogens and toxic
protein aggregates. The roles of TNTs in pathological spreading of several neurodegenerative conditions such as
Prion diseases, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) have been well
established. However, the fragile nature of these structures and lack of specific biomarkers raised some skepticism
regarding their existence. In this review, we will first place TNTs within the spectrum of intercellular
communication mechanisms before discussing their known and hypothesized biological relevance in vitro and in
vivo in physiological and neurodegenerative contexts. Finally, we discuss the challenges and promising prospects in
the field of TNT studies.

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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