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

Table 3. (Continued)
SARS‑CoV‑2 Function in SARS‑CoV‑2 replication Plausible mechanism contributing References
proteins to neurodegeneration
Nsp14 Shows exoribonuclease activity; involved RNA capping N7 methyltransferase activity mimics 70,137,139
the cap structure on the true viral
RNA, thus making it unrecognized
by the host immune system for a long
period of time
Nsp15 Endoribonuclease activity, cleaving RNA substrate at the Escaping host detection ensures viral 71,137,139
3’ of uridines, evading detection by the innate immune persistence for a longer time in brain
response cells
Nsp16 Responsible for methylating the 5’-end of viral mRNAs, Ensure viral persistence in the brain 70,137,139
generating cap1 structures that shield viral mRNA from and compromised immune response;
MDA5 recognition promote viral replication and
neurodegeneration
Spike Virus-host cell membrane fusion protein binds to ACE2 Highest affinity towards ACE2 137,139
and co-receptors receptors on the cell surface, thus
promoting viral invasion and
persistence in the brain; Nsp1
binds to the cleaved S1 domain of
S protein and amplifies the process
of internalization, inducing lipid
modification, which may impact BBB
permeability
Nucleocapsid Viral genome packaging binds to chemokines with the May promote chronic 137,139
ability to block chemotaxis of immune effector cells neuroinflammation by blocking the
chemotaxis of immune effector cells
Envelope Viroporin functions as a ligand for TLR2, promotes May promote chronic 137,139
cytokine production, and has an impact on spike protein neuroinflammation and ER-stress
processing and maturation by promoting its retention in
the ER-Golgi intermediate compartment
Membrane Inhibit IFN-antiviral response; interacts with RIG-I/ May promote chronic 73,74,137,139
MDA-5-MAV neuroinflammation
Orf3a Viroporin is involved in virus replication; activates NLRP3 Activation of NLRP3 inflammasome 137,139
inflammasome complex and IL-1β release; promotes may result in microglial activation
phagophore nucleation by favoring PI3KC3-C1 formation; and pyroptotic cell death or
activates UPR by activating ATF6; promotes the activation sustained pro-inflammatory response
of NF-κB, TLR3 or TLR4, promotes the production associated with age-associated
of HIF-1α through the generation of ROS in the neurodegeneration.
mitochondria and subsequent mitochondrial disruption;
enhances the production of pro-inflammatory cytokines
IFN-β, IL-6, and IL-1β.
Orf3b IFN antagonist Promote chronic neuroinflammation 75,137,139
Orf3c ORF3c localizes to mitochondria and interacts with Mitochondrial dysfunction may lead 75,137,139
both MAVS and PGAM5 (mt serine/threonine protein to ROS production and impaired
phosphatase); ORF3c expression leads to a reduction in glycolysis, leading to neuronal death
IFNB transcripts and IFN-β protein levels or deregulation
Orf3d Suppress immune activation by an unknown mechanism 137,139
Orf6 Binds to NPC proteins (Nup98-Rae1) to inhibit STAT1 and Generate immune compromised 75,76,137,139
IRF3 cytosolic-nuclear translocation thus blocking IFN microenvironment; induce chronic
signaling; neuroinflammation
Orf7a Interacts with human CD14 monocytes, leading to Altered cytokine and chemokine 137,139
+
the limitation of antigen presentation; promotes the profiles may induce CNS as well as
up-regulation of certain chemokines such as CCL11, PNS dysfunction, including cognitive
CCL17, CCL19, CCL21, CCL22, CCL25, CCL26, CCL27 and motor impairments
(Cont’d...)

Volume 3 Issue 4 (2024) 11 doi: 10.36922/an.4267