6. The Prion Protein and Autophagy
An impairment or failure of macro-autophagy is being increasingly recognized as a primary contributor to prion disease [61,62]. In a paper published in 2020 by a team of researchers in Spain, the authors wrote in the abstract: “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.” [63]. Macro-autophagy is an important pathway by which misfolded prion protein itself is degraded, and drugs that induce autophagy have been shown to have anti-prion effects [64]. Autophagic vacuoles normally form and then fuse with endolysosomes for eventual clearance [65]. With increased autophagy activity, the neuron is less likely to release prion proteins within exosomes to induce spread of infectivity to other neurons [64]. Interestingly, the prion protein is upregulated under multiple stressed conditions, and it has been proposed that an important role it plays is to facilitate the fusion of the autophagosomes with lysosomes to promote clearance of cellular debris – including misfolded proteins and damaged mitochondria.
There exist strains of mice used in research laboratories that have a genetic mutation in the prion protein gene which disables its expression. These mice provide important knowledge about the functions of the prion protein by virtue of its absence. A key feature of these mice is the appearance very early in life of autophagic vacuoles in the cytoplasm. Vacuoles appeared as early as 3 months of age in cortical neurons, and by 6 months they had also appeared in hippocampal neurons. The number of vacuoles increased in the hippocampus at an accelerated rate with aging compared to control mice. These defective mice were more sensitive to oxidative stress, and they had an increased risk to seizures, motor and cognitive abnormalities, and impaired long-term potentiation in the hippocampus [66]. These mice provide strong support for the view that the prion protein supports autophagic clearance of cellular debris.
Curiously, autophagic vacuoles are also a common feature of neurodegenerative disease, including Creutzfeldt Jakob Disease (CJD) [62]. The facts that both too little and too much prion protein lead to similar disease states can be explained if we assume that prion disease is mainly a loss-of-function pathology. When the neuron is exposed to stressors that increase the burden of misfolded proteins, it upregulates PrP to assist in the removal of this debris via the lysosomal system. But once there are seed misfolded PrPSC proteins, or externally supplied misfolded prion-like proteins such as the spike protein, along with the high concentration of PrP induced by the stressors, there is the potential for the seed to recruit most of the PrP present in the cytoplasm, converting it first to soluble oligomers and finally to precipitated fibrils. While the amount of PrP in the cell is high, most of it is tied up in the oligomers and fibrils, so it is no longer able to clear the debris, resulting in the accumulation of vacuoles.