Protein Quality Control Systems and ER Stress as Key Players in SARS-CoV-2-Induced Neurodegeneration

Abstract

The COVID-19 pandemic has brought to the forefront the intricate relationship between SARS-CoV-2 and its impact on neurological complications, including potential links to neurodegenerative processes, characterized by a dysfunction of the protein quality control systems and ER stress. This review article explores the role of protein quality control systems, such as the Unfolded Protein Response (UPR), the Endoplasmic Reticulum-Associated Degradation (ERAD), the Ubiquitin–Proteasome System (UPS), autophagy and the molecular chaperones, in SARS-CoV-2 infection. Our hypothesis suggests that SARS-CoV-2 produces ER stress and exploits the protein quality control systems, leading to a disruption in proteostasis that cannot be solved by the host cell. This disruption culminates in cell death and may represent a link between SARS-CoV-2 and neurodegeneration.

Effect of Melatonin on Herpesvirus Type 1 Replication

“…The absence of viral machinery for protein synthesis, which makes the virus completely dependent on the cellular machinery for the production of its own proteins, makes the endoplasmic reticulum, as the cell's main protein producer, a prime candidate for study. Thus, the new viral demand for proteins will induce an excess of endoplasmic request that will result in an overproduction of misfolded proteins known as endoplasmic reticulum stress [4], which usually exceeds the capacity of the proteasome. To try to counteract this stress, the cell develops its multifactorial misfolded protein response system (known as UPR) which triggers consecutive response cascades depending on the severity of the induced stress [5] and which may ultimately induce the activation of survival mechanisms, such as autophagy or programmed cell death or apoptosis.…”

Effect of Melatonin on Herpesvirus Type 1 Replication

“…The absence of viral machinery for protein synthesis, which makes the virus completely dependent on cellular machinery for the production of its own proteins, makes the endoplasmic reticulum, as the cell's main protein producer, a prime candidate for study. Thus, the new viral demand for proteins will induce an excess of endoplasmic request that will result in an overproduction of misfolded proteins known as endoplasmic reticulum stress [4], which usually exceeds the capacity of the proteasome. To try to counteract this stress, the cell develops its multifactorial misfolded protein response system (known as unfolded protein response, UPR), which triggers consecutive response cascades depending on the severity of the induced stress [5] and may ultimately induce the activation of survival mechanisms, such as autophagy or programmed cell death or apoptosis.…”