Cellular mechanisms responsible for cell-to-cell spreading of prions

Abstract

Prions are infectious agents that cause fatal neurodegenerative diseases. Current evidence indicates that they are essentially composed of an abnormally folded protein (PrP). These abnormal aggregated PrP species multiply in infected cells by recruiting and converting the host PrP protein into new PrP. How prions move from cell to cell and progressively spread across the infected tissue is of crucial importance and may provide experimental opportunity to delay the progression of the disease. In infected cells, different mechanisms have been identified, including release of infectious extracellular vesicles and intercellular transfer of PrP-containing organelles through tunneling nanotubes. These findings should allow manipulation of the intracellular trafficking events targeting PrP in these particular subcellular compartments to experimentally address the relative contribution of these mechanisms to in vivo prion pathogenesis. In addition, such information may prompt further experimental strategies to decipher the causal roles of protein misfolding and aggregation in other human neurodegenerative diseases.

Bidirectional Microglia–Neuron Communication in Health and Disease

“…EVs contain different bioactive compounds including cell surface receptors, mitochondrial and cytosolic proteins, metabolic enzymes and genetic materials such as microRNAs and mRNAs ( Abels and Breakefield, 2016 ; Dozio and Sanchez, 2017 ; Prada et al, 2018 ). Additionally, EVs could carry pathological markers, such as α-synuclein, tau, amyloid beta (Aβ) ( Rajendran et al, 2006 ; Ngolab et al, 2017 ; Valdinocci et al, 2017 ) and pathogenic prion proteins ( Schneider and Simons, 2013 ; Vilette et al, 2018 ) as well as huntingtin ( Zhang et al, 2016 ; Deng et al, 2017 ) that implicate exchange of EVs in pathological conditions. EVs are able to influence the behavior of recipient cells in multiple ways: they may transfer receptors and/or bioactive lipids between cells; they can modulate functional target cells by delivering intracellular proteins or transferring mRNA; and may act as signaling complexes through the stimulation of target cells ( Basso and Bonetto, 2016 ).…”

Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases

“…The potential for deleterious functions of EV movement between cells was initially based upon the idea that EVs can efficiently transfer pathogens between cells. In the brain, one such pathogenic molecule that uses EV release is misfolded prion protein (PrP), causing transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in cattle Vilette et al, 2018). α-synuclein, involved in the pathogenesis of Parkinson's disease, is also secreted in a calcium-dependent manner via EVs (Emmanouilidou et al, 2010;Alvarez-Erviti et al, 2011;Danzer et al, 2012;Stuendl et al, 2016;Ngolab et al, 2017), and the transfer of α-synuclein fibrils between cells appears to be an important component of α-synuclein pathology, spread of the misfolded protein to distant sites, and the activation of immune cells (reviewed in Tofaris, 2017;Grozdanov and Danzer, 2018;Stefanis et al, 2019).…”

Unconventional Secretion and Intercellular Transfer of Mutant Huntingtin

“…Abnormally folded PrPSc could multiply in cells by interacting with and driving the conformational conversion of cellular PrP C to PrP Sc . The cellular mechanisms responsible for the cell-to-cell spreading of prions has recently been reviewed in detail by Vilette and colleagues [ 120 ].…”