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.

Reflections on Cerebellar Neuropathology in Classical Scrapie

“…The spongiosis (micro- and macrovacuolization) observed in this pathology, a differential characteristic of the group of transmissible spongiform diseases, has not been well elaborated thus far, although it is of great importance in diagnosis [ 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. In studies at the level of optical and electron microscopy, a large number of vacuoles with a size of 0.3 to 20 microns have been evidenced, outside the neurons in the neuropil.…”

“…Autophagy seems to be decreased in the late phases of the scrapie disease. In PCs, the autophagy machinery is still intact in less affected areas [ 80 , 81 ] and, probably, induces PrPsc clearance. These adaptive or pathological structures are not specific to scrapie and can be observed in senile animals or in other pathologies.…”

“…The most frequently referenced are aggresomes, which are round electron-dense structures and not membrane-bound [ 81 ]; tubulovesicular structures (TVS, vesicular structures of higher electron density than synaptic vesicles, of approximately 27 nm in diameter within axonal terminal or dendrites) of unknown significance; electron-dense bodies; “whorls” or concentric arrays of membranes; debris of apoptotic cell nuclei, etc. [ 76 , 81 , 82 , 83 , 84 , 85 , 86 , 87 ]. It should also be noted that in normal sheep, many smooth endoplasmic reticulum formations are observed in the soma and dendrites of PCs (“spine apparatus”, hypolemmal cisterns), which can give rise to very extensive tubulovesicular formations of unknown significance, although they are not necessarily pathological.…”

“…The evolution of areas of high synapse concentration in scrapie has been reported in several experimental studies. In different neuronal types, especially in Purkinje neurons, various types of morphological alterations have been shown (as mentioned above), especially at the level of EM, and they have been interpreted in different ways over the years [ 76 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]. Some alterations (especially the so-called “tubulovesicular structures”) were primarily considered to be specific for prion diseases but were later “declassified” as pathognomonic markers of the disease [ 84 , 85 , 86 , 87 ].…”

Therapeutic Assay with the Non-toxic C-Terminal Fragment of Tetanus Toxin (TTC) in Transgenic Murine Models of Prion Disease

“…The aim of the present study was to test TTC as a potential therapy for prion diseases. Considering the impact of autophagy and apoptosis in both prion diseases [36] and ALS [34,37], in which TTC has shown therapeutic results, and the potential of TTC as an anti-apoptotic and autophagy-regulator molecule, we assessed the apoptotic and autophagic mechanisms in the CNS of prion diseased murine models treated with TTC.…”