Journal Article

Neuroproteomic Analysis after SARS-CoV-2 Infection Reveals Overrepresented Neurodegeneration Pathways and Disrupted Metabolic Pathways

Basak, Indranil, Harfoot, Rhodri, Hughes, Stephanie M., Palmer, Jennifer E., Schweitzer, Lucia, Quiñones-Mateu, Miguel E., Kumar, Abhishek

2023

Overview

Besides respiratory illness, SARS-CoV-2, the causative agent of COVID-19, leads to neurological symptoms. The molecular mechanisms leading to neuropathology after SARS-CoV-2 infection are sparsely explored. SARS-CoV-2 enters human cells via different receptors, including ACE-2, TMPRSS2, and TMEM106B. In this study, we used a human-induced pluripotent stem cell-derived neuronal model, which expresses ACE-2, TMPRSS2, TMEM106B, and other possible SARS-CoV-2 receptors, to evaluate its susceptibility to SARS-CoV-2 infection. The neurons were exposed to SARS-CoV-2, followed by RT-qPCR, immunocytochemistry, and proteomic analyses of the infected neurons. Our findings showed that SARS-CoV-2 infects neurons at a lower rate than other human cells; however, the virus could not replicate or produce infectious virions in this neuronal model. Despite the aborted SARS-CoV-2 replication, the infected neuronal nuclei showed irregular morphology compared to other human cells. Since cytokine storm is a significant effect of SARS-CoV-2 infection in COVID-19 patients, in addition to the direct neuronal infection, the neurons were treated with pre-conditioned media from SARS-CoV-2-infected lung cells, and the neuroproteomic changes were investigated. The limited SARS-CoV-2 infection in the neurons and the neurons treated with the pre-conditioned media showed changes in the neuroproteomic profile, particularly affecting mitochondrial proteins and apoptotic and metabolic pathways, which may lead to the development of neurological complications. The findings from our study uncover a possible mechanism behind SARS-CoV-2-mediated neuropathology that might contribute to the lingering effects of the virus on the human brain.

• Publisher: MDPI AG
• Subject: Apoptosis / Brain / COVID-19 / Culture Media, Conditioned / Cytokine storm / Cytology / Degeneration / Disease transmission / Encephalitis / Humans / Hypoxia / Immunocytochemistry / Infections / iPSC-derived human neurons and astrocytes / mass spectrometry / Membrane Proteins / Metabolic Networks and Pathways / Metabolic pathways / Molecular modelling / Nerve Tissue Proteins / Nervous system / Neural stem cells / NeuroCOVID / Neurodegeneration / Neurological complications / Patients / Pluripotency / Proteomics / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Stem cells / Stroke / Transcription factors / Virions