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Advanced Neurology SARS-CoV-2 in age-associated neurodegeneration

Interestingly, the SARS-CoV-2 protein ORF3a is 6.3. Proteostasis perturbations in long-term COVID
involved in the activation of hypoxia-inducible factor and accelerated brain aging
1-α (HIF1α) by inducing mitochondrial damage and Proteostasis is a critical factor in the interplay between
the production of mitochondrial ROS. HIF1α, a master viral infection and the onset of neurodegenerative
regulator of glycolysis and other metabolic pathways, diseases. Viruses, including SAR-CoV-2, often manipulate
subsequently enhances viral replication and the pro- host proteostasis mechanisms to facilitate their own
inflammatory response. Ajaz et al. investigated translation. Upon infection with COVID-19 infection,
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functional alterations in mitochondria within living increased inflammatory response, ROS generation, and
peripheral blood mononuclear cells from patients with endoplasmic reticulum (ER) stress due to high viral protein
COVID-19, revealing changes in the immune system expression lead to elevated levels of heat shock proteins,
that suggests oxidative stress mediated by mitochondrial triggering cellular apoptosis and necrosis. Unfolded protein
dysfunction contributes to inflammaging-like features
in long-term COVID situations. In addition, Prasada response (UPR) is primarily driven by three different
Kabekkodu et al. have suggested that SARS-CoV-2 factors, including protein kinase R-like ER kinase (PERK),
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proteins may localize in the mitochondria, increasing inositol-requiring enzyme 1α, and activating transcription
mitochondrial leakage and interfering with Ca signaling. factor 6 (ATF6), all of which respond to ER-membrane
2+
Calcium homeostasis plays a crucial role in synaptic stress. Dysregulation of ER stress-induced UPR plays a
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transmission, synaptic plasticity, apoptosis, and cell critical role in age-related neurodegeneration. Emerging
survival, all of which may be linked to cognitive decline evidence suggests that the spike protein of SARS-CoV-2,
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and motor dysfunction. 104 or ORF8, is sufficient to activate UPR. Conversely, the
N-terminal fragment of NSP3, namely NSP3.1, interacts
An emerging theory describes how MAVs binding to with ATF6 and suppresses ATF6-mediated UPR pathways.
RIG-I inhibits the interaction of MAVs with hexokinase, Similarly, MHV triggers the activation of X-box binding
thereby impairing glycolysis. Carpenè et al. protein 1 and the PERK pathway, while hindering UPR-
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have demonstrated that lactate levels in the blood of responsive genes such as pro-apoptotic transcription factor
COVID-19 patients were significantly higher than those C/EBP homologous protein (CHOP). In acute COVID-
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of control subjects. Since cells of the CNS have high 19 patients, host heat shock proteins, such as GRP78,
energy demands, such disruptions in energy metabolism GRP94, binding IgG protein, protein disulfide isomerase,
due to viral infection not only prolong the presence of calreticulin, and calnexin, are required for the rapid
viral components in the body but also promote slow and replication of viral proteins. However, excessive viral
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persistent neurodegeneration. Furthermore, the induction protein expression increases the percentage of unfolded
of pattern recognition receptors and the IFN-1 signaling and misfolded proteins in the ER lumen, inducing ER
pathway leads to increased ROS production by xanthine stress and UPR. Deregulation of proteostasis pathways
oxidase, nitric oxide synthase, and the mitochondrial due to high viral replication can lead to the formation
respiratory response. SAR-CoV-2 can activate NADPH of oligomers, amorphous aggregates, and amyloid
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oxidase 2 through toll-like receptor-7, which inhibits fibers, which are clinical hallmarks of age-associated
the immune response while increasing ROS levels and neurodegenerative diseases. A recent report by Lee et al.
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supporting viral infection. This overproduction of has described the upregulation of apoptosis-associated
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ROS can lead to the oxidation of phospholipids and genes, such as FAS-associated protein with death domain,
macromolecules, altering BBB permeability. In particular, Bcl-2-like protein 4 (BAX), BH3 interacting death domain,
the binding of the viral spike protein to ACE2 leads to and Caspase 9, as well as autophagy-regulating genes such
excessive production of angiotensin II, which activates as WD-repeat β-propeller 45 protein and tectonin beta-
NADPH oxidase, further enhancing oxidative stress. propeller repeat containing 2 in human dopaminergic
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The production of excessive cytokines, including IL-1β, neurons following human preformed fibril treatment.
IL-2, and IL-6, stimulates ROS, reactive nitrogen species, These effects were further amplified with SARS-CoV-2
and the formation of oxygen radicals. According to the infection. In contrast, the expression of key autophagy
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“free radical theory” of aging, the accumulation of ROS marker proteins, such as microtubule-associated proteins
not only accelerates aging but also impairs protein folding 1A/1B light chain 3B and sequestosome-1 (SQSTM1/P62),
responses, potentially leading to cognitive and motor was downregulated upon SARS-CoV-2 infection.
deficits. Overall, it can be speculated that the persistence
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of SARS-CoV-2 and its components in the brain induces Although direct evidence linking proteostasis
a vulnerable state that may accelerate the onset of age- deregulation to long COVID-related neurological
related neurodegeneration. manifestations remains insufficient, it is clear that ER

Volume 3 Issue 4 (2024) 14 doi: 10.36922/an.4267