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.