Prion aggregates transfer through tunneling nanotubes in endocytic vesicles

Abstract

ABSTRACT. Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases caused by the misfolding of the cellular prion protein to an infectious form PrP Sc . The intercellular transfer of PrP Sc is a question of immediate interest as the cell-to-cell movement of the infectious particle causes the inexorable propagation of disease. We have previously identified tunneling nanotubes (TNTs) as one mechanism by which PrP Sc can move between cells. Here we investigate further the details of this mechanism and show that PrP Sc travels within TNTs in endolysosomal vesicles. Additionally we show that prion infection of CAD cells increases both the number of TNTs and intercellular transfer of membranous vesicles, thereby possibly playing an active role in its own intercellular transfer via TNTs.

Transfer of disrupted-in-schizophrenia 1 aggregates between neuronal-like cells occurs in tunnelling nanotubes and is promoted by dopamine

“…In the co-culture system used here, we observed no transmission by supernatant or in the condition of co-culture filter, indicating that the intercellular transfer of DISC1 aggregates is not mediated by secretion and requires cell-to-cell contact. As previously shown for prion and other proteins involved in neurodegenerative diseases [29,30,38,39,56,57], we found that DISC1 aggregates can also transfer between cells through TNTs. This was also supported by the finding that the efficiency of transfer was increased upon induction of TNT formation by Myo10, a positive regulator of TNTs, and reduced by VASP, a negative regulator of TNTs.…”

“…Compared to proteins related to neurodegenerative diseases, the efficiency of transfer of DISC1 aggregates is lower [29,30,56,58,59]. The inefficient transmission of DISC1 aggregates may be due to the low cell invasiveness and limited movement of these aggregates as previously reported [17,42].…”

Differential identity of Filopodia and Tunneling Nanotubes revealed by the opposite functions of actin regulatory complexes

“…TNTs are also emerging as an important player in cancer development561213. We have previously demonstrated that TNTs can mediate the intercellular transfer of infectious prions between neuronal cells, dendritic cells to neurons, and between astrocytes14151617. Interestingly, other “prion-like” amyloidogenic proteins like misfolded huntingtin18, amyloid β19, α-synuclein20, and tau21 can also be transferred between distant cells through TNTs, thus underscoring the important role of TNTs in the progression of neurodegenerative diseases, and their potential use as therapeutic targets22.…”

Tumor microtubes connect pancreatic cancer cells in an Arp2/3 complex-dependent manner

“…First, pathogens such as viruses (Sowinski et al, 2008;Hashimoto et al, 2016;Kumar et al, 2017;Panasiuk et al, 2018) and bacteria (Önfelt et al, 2006;Kim et al, 2019) can use IMTs as a means of cell-to-cell transfer. Second, mis-folded protein aggregates including huntingtin (Costanzo et al, 2013), prion protein (Zhu et al, 2015), and -synuclein (Abounit et al, 2016) have also been shown to transfer between cells through IMTs. Finally, IMTs have been linked to increased treatment resistance of several cancers.…”