Related Experiment Video

Updated: Aug 2, 2025

Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles
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Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles

Published on: October 18, 2024

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SARS-CoV-2 ORF3a expression in brain disrupts the autophagy-lysosomal pathway, impairs sphingolipid homeostasis, and

Hongling Zhu1, Colleen Byrnes1, Y Terry Lee1

  • 1Genetics of Development and Disease Section, Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|April 18, 2023
PubMed

Insights

The SARS-CoV-2 accessory protein ORF3a drives brain damage in COVID-19 by disrupting cellular processes. This protein causes neurodegeneration and neuroinflammation, contributing to both short- and long-term neurological issues.

Area of Science:

  • Neuroscience
  • Virology
  • Cell Biology

Background:

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection impacts multiple organs, including the brain, but the precise neuropathological mechanisms remain unclear.
  • Potential mechanisms include systemic inflammation, hypoxia, and direct viral damage to neurons and glial cells.

Purpose of the Study:

  • To investigate the neuropathological effects of SARS-CoV-2 open reading frame 3a (ORF3a), a key viral accessory protein.
  • To understand how ORF3a contributes to acute and long-term brain injury in COVID-19.

Main Methods:

  • Forced expression of ORF3a in mouse brains to observe neurological and pathological changes.
  • Utilized ORF3a-expressing HeLa cells to study its effects on cellular pathways.

Main Results:

  • ORF3a brain expression in mice led to rapid neurological impairment, neurodegeneration, and neuroinflammation.
  • ORF3a blocked autophagy progression and caused neuronal accumulation of α-synuclein and glycosphingolipids.
  • ORF3a disrupted the autophagy-lysosomal pathway and inhibited glycosphingolipid degradation in HeLa cells.

Conclusions:

  • SARS-CoV-2 ORF3a expression in brain cells can drive neuropathogenesis.
  • ORF3a may be a critical mediator of both short-term and long-term neurological manifestations of COVID-19.

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