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Page 34 Chakraborty et al. Extracell Vesicles Circ Nucleic Acids 2023;4:27-43 https://dx.doi.org/10.20517/evcna.2023.05

[98]
macrophages . Recently, SARS-CoV-2 has been shown to utilize TNTs to spread between permissive
[46]
epithelial and non-permissive neuronal cells , implicating a potential role of these structures in the
manifestation of neurological symptoms upon viral infection.

TUNNELING NANOTUBES VERSUS EVS IN THE SPREAD OF NEURODEGENERATIVE
PATHOLOGIES
With accumulation of protein aggregates and concomitant compromise of quality control pathways in
NDs , burdened cells remain far from homeostasis. The inability of post-mitotic cells like neurons to dilute
[99]
out these protein aggregates eventually leads to their degeneration, besides the non-cell-autonomous effects
of glial cells in neurotoxicity . With the progression of the pathologies (Braak’s stages) , degeneration
[99]
[100]
spreads from the epicenter of initial aggregate seeding to different regions of the brain. A major mechanism
of such spreading is via secretory pathways, with the release of protein aggregates in extracellular vesicles
that are eventually internalized by other cells. The close association of protein aggregates with exosomes has
been reported for several NDs (reviewed in ). Both soluble and aggregated forms of Prion (PrP and
[100]
C
PrP , respectively) associate with exosomes, with PrP causing aggregation in the acceptor cell . In
[101]
Sc
Sc
Alzheimer’s disease (AD), both tau and amyloid precursor protein (APP), associated metabolites and
secretase enzymes have been shown to be present in exosomes [102,103] . Parkinson’s disease (PD) causing α-Syn
[104]
can be packaged within exosomes and eventually secreted . Such exosomes are internalized by
neighboring cells, preferably over isolated oligomers not associated with exosomes . In Amyotrophic
[105]
Lateral Sclerosis (ALS), both WT and mutant Superoxide dismutase (SOD1) associate with exosomes and
are released by both neurons and astrocytes in vitro and in vivo [106-108] . Exosomes have also been reported to
transport transcripts of mutant huntingtin (mHtt), besides the protein itself, in the case of HD [109,110] .
Although these studies confirm the propagative roles of exosomes in different NDs, it is important to note
that purification and/or concentration of secreted vesicles does not represent the true extent of secretion-
mediated transfer. Additionally, secretion-based mechanisms are not the exclusive routes for the spread of
such pathologies. In the subsequent sections, we discuss a parallel mechanism in place for aggregate transfer
between cells.

A major shift in the paradigm of neurodegenerative pathology spreading happened when TNTs were shown
Sc
to transfer PrP between neuronal cells . This study paved the way for several subsequent reports on
[97]
different types of protein aggregates utilizing TNTs as a route for spreading to neighboring cells, both
neuronal and non-neuronal [Figure 3A-B, and Table 1]. Not only are different aggregates transferred
between cells, but there also happens an increase in the extent of TNT-mediated intercellular connectivity in
the presence of neurotoxic aggregates. As such, an existent dogma in the field suggests that protein
aggregates increase TNTs as a way of increasing transmissivity between cells. We and others have proposed
that this phenomenon might be linked to an increase in ROS species in cells burdened with toxic
aggregates . However, more studies will be needed to understand the precise mechanism(s) and molecular
[48]
pathways leading to TNT increase in these conditions.

Prion’s Diseases
Prion proteins can cause Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS),
and fatal familial insomnia (FFI) in humans. Over the years, prions have gained considerable attention
because of their ability to be transmitted from animals to humans, as seen in the case of bovine spongiform
Sc
encephalopathy (BSE) . The aggregate-prone form of Prion, PrP , has been reported to transfer via TNTs
[111]
not only between neuronal cells, but also between bone marrow-derived dendritic cells and primary
neurons [97,112] . PrP increases the formation of TNTs between neighboring cells, possibly by causing ER
Sc
stress and differential distribution of membrane cholesterol, and eventually makes its way to a different cell