Identification of a SARS-CoV2 viral protein that triggers neurodegeneration and accelerates Aβ42 mediated neurodegeneration

Identification of a SARS-CoV2 viral protein that triggers neurodegeneration and accelerates Aβ42 mediated neurodegeneration

Presenter(s)

Aditi Singh, Anuradha Chimata Venkatakrishnan

Comments

Presentation: 1:15-2:30 p.m., Kennedy Union Ballroom

Description

The SARS-CoV2 virus is responsible for the recent COVID-19 Pandemic that caused a range of symptoms including an acute respiratory tract infection up to fatal severe acute respiratory syndrome (SARS) that is fatal. The virus is highly contagious, rapidly mutating, and has resulted in massive morbidity and mortality around the globe including within the United States and worldwide. While COVID-19’s acute symptoms are known, the long-term sequelae and impacts like Post COVID-19 Syndrome (PCS) are lesser known and remain understudied. To date, it is understood that SARS-CoV2 results in an increased inflammatory response, cognitive dysfunction like brain fog, several long-term cardiovascular and autoimmune changes. Therefore, we hypothesized that SARS-CoV2 may impact conditions with pre-existing neuroinflammation, neurodegeneration, and cognitive dysfunction like Alzheimer’s Disease (AD). To study these impacts, we used the Drosophila melanogaster, or fruit fly model, to understand how specific SARS-CoV2 proteins affect neurodegenerative pathology. Our model first misexpressed specific SARS-CoV3 CoV2 proteins in wildtype flies via Gal4-UAS system. Interestingly, misexpression of SARS-CoV2 NSP3, nonstructural protein 3 (NSP3), generated a rough eye phenotype with necrotic spots indicating cell death. These findings suggested that COVID-19 alone may promote cell death. We also confirmed these results in the mammalian neuronal cell known as Neuro-2a cells. Transient expression of SARS-CoV2 NSP3 significantly reduced the metabolic activity of these cells and enhanced cell death (p < 0.05). We were interested in observing how COVID-19 may potentiate cell death in a neurodegenerative background that has high pre-existing levels of neuroinflammation and cell death. Therefore, we misexpressed SARS-CoV2 NSP3 in an AD transgenic fly using the Gal4-UAS system (GMR>Aβ42). Here, we observed a worsening of the rough eye phenotype and increased cell death. Changes in cell morphology and increases in cell death may be indicative of COVID-19-mediated changes to AD pathophysiology. These findings suggested that a cell death mechanism may be involved in COVID-19 mediated worsening in AD pathology. Here, we present our studies in assessing various cell death mechanisms including autophagy, apoptosis, and necrosis, and their potential involvement in SARS-CoV2’s impacts on AD pathology.

Publication Date

4-19-2023

Project Designation

Graduate Research

Primary Advisor

Amit Singh, Mrigendra Rajput

Primary Advisor's Department

Biology

Keywords

Stander Symposium, College of Arts and Sciences

Institutional Learning Goals

Scholarship

Identification of a SARS-CoV2 viral protein that triggers neurodegeneration and accelerates Aβ42 mediated neurodegeneration

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