An Update on Autophagy in Prion Diseases

Abstract

Autophagy is a dynamic intracellular mechanism involved in protein and organelle turnover through lysosomal degradation. When properly regulated, autophagy supports normal cellular and developmental processes, whereas defects in autophagic degradation have been associated with several pathologies, including prion diseases. Prion diseases, or transmissible spongiform encephalopathies (TSE), are a group of fatal neurodegenerative disorders characterized by the accumulation of the pathological misfolded isoform (PrP^Sc) of the physiological cellular prion protein (PrP^c) in the central nervous system. Autophagic vacuoles have been described in experimental models of TSE and in the natural disease in humans. The precise connection of this process with prion-related neuropathology, or even whether autophagy is completely beneficial or pathogenic during neurodegeneration, is poorly understood. Thus, the biological role of autophagy in these diseases is still open to debate. During the last years, researchers have used a wide range of morphological, genetic and biochemical methods to monitor and manipulate the autophagic pathway and thus determine the specific role of this process in TSE. It has been suggested that PrP^c could play a crucial role in modulating the autophagic pathway in neuronal cells, and the presence of abnormal autophagic activity has been frequently observed in several models of TSE both in vitro and in vivo, as well as in human prion diseases. Altogether, these findings suggest that autophagy is implicated in prion neuropathology and points to an impairment or failure of the process, potentially contributing to the pathogenesis of the disease. Additionally, autophagy is now emerging as a host defense response in controlling prion infection that plays a protective role by facilitating the clearance of aggregation-prone proteins accumulated within neurons. Since autophagy is one of the pathways of PrP^Sc degradation, and drug-induced stimulation of autophagic flux (the dynamic process of autophagic degradation activity) produces anti-prion effects, new treatments based on its activation have been tested to develop therapeutic strategies for prion diseases. In this review, we summarize previous and recent findings concerning the role of autophagy in TSE.

Keywords: Creutzfeldt-Jakob disease; LC3; autophagy; neurodegenerative diseases; p62; prion diseases; scrapie; therapies.