12. The Fine Balance between Autophagy and Proteasome
Degradation in Relation to Neurodegeneration
A common characteristic of neurodegenerative diseases is a severe
disturbance of protein homeostasis. Impaired clearance of misfolded
proteins via autophagy/lysosomal degradation results in their
accumulation within the cytoplasm [105].
p53 has multi-functional roles in macro-autophagy (hereafter termed as
autophagy), a state where the cell suppresses cellular regeneration and
consumes/recycles intracellularly its constituents to maintain
homeostasis and survival during starvation. Autophagy and p53 exhibit
reciprocal functional interactions. p53 operates within a negative
feedback loop with the process of autophagy: as p53 activity increases,
autophagy is activated within the cell. With increased autophagy,
negative feedback suppresses the activity of p53 [106]. During
autophagy activation, the intracellular components are delivered to
lysosomes for further degradation via both macro- and micro-autophagy
pathways, as described in detail by Barbosa et al. [107].
The ubiquitin-proteasome system (UPS) and autophagy are two
interconnected pathways that mediate the degradation of misfolded
proteins. Sequestosome-1, also known as the ubiquitin-binding protein
p62, plays a critical role in both pathways. p62 captures and presents
ubiquitinated cargos for autophagy [108]. Decreased levels of p62
are linked to many neurodegenerative diseases [109]. Oxidative
damage to the p62 promoter decreases p62 promoter activity, reducing
expression of p62, and therefore impairing autophagy. Its promoter is
particularly rich in guanines that are especially susceptible to
oxidative damage [109]. The inhibition of proteasome degradation
results in impaired clearing of substrates such as p53 and β-catenin,
and this results in a twofold increase in their levels in cellular
models. These same elevated levels are reached when the UPS is blocked,
even when autophagy is not inhibited.
Since many UPS substrates such as p53 mediate toxicity, impaired removal
of such regulatory proteins via autophagy is recognized as a
prerequisite for many severe disease states, such as in the case of
prion disease, solely due to intracellular increase of aggregation-prone
proteins [73]. Furthermore, the activation of autophagic mechanisms
is lowered with advancing age, constituting an extra parameter for
susceptibility to neurodegenerative disease due to autophagic inhibition
[107].
With respect to the development of prion disease, specific in
vitro and in vivo models have shown that reduced gene expression
of p38 MAPK facilitated the clearance of BACE-1 through lysosomal
degradation. This resulted in a decrease in the intracellular level and
activity of BACE-1, and, ultimately, lower Aβ levels in the mouse brain,
associated with enhanced autophagic mechanisms. Thus, knockdown of p38
MAPK in neurons reduces Aβ generation and decreases Aβ load by promoting
macroautophagy. Moreover, in a separate experiment, the authors treated
human cells with an autophagy inhibitor, and this also increased BACE-1
protein levels, and even abolished the p38-MAPK knockdown-induced
decrease of BACE-1 protein. These findings demonstrate that p38 MAPK
activation and autophagy inhibition are vital for the progression of
prion disease [110].
In relation to SARS CoV-2 spike protein being a toxic factor for prion
disease, these findings are of major importance, since infectious prions
are shown to activate the p38 MAPK signaling response. In an equal
fashion, and in a dose dependent manner, the S1 subunit of the spike
protein has been shown to a) increase p38 MAPK protein levels, b)
increase phosphorylated p38 levels, c) increase the inflammatory
cytokines IL-6 and TNF-α, amongst others, d) increase TLR2/4 protein
levels and thus signaling, and e) increase NF-κB protein activity and
binding to provide transcriptional control over the established
neuroinflammation in S1-induced BV2 microglia [13,10].