ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2023
SARS-CoV-2 ORF3a expression in brain disrupts the autophagy-lysosomal pathway, impairs sphingolipid homeostasis, and drives neuropathogenesis.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 19 citations in OpenAlex.
- The accessory protein ORF3a hijacks the CLCC1 chloride channel to disrupt ER homeostasis in betacoronavirus pathogenesis.Cell discovery · 2026Article
- SARS-CoV-2 Delta variant-specific ORF3a mutations destabilize lysosomal homeostasis to trigger lysosomal damage-mediated cell death.Communications biology · 2026Article
- From HIV to SARS-CoV-2 associated neurological disorder ("HAND" to "SAND"): Viral infection as a "time-bomb" for the aging brain.Neuroscience applied · 2026Review
- Disease-disease interactions: molecular links of neurodegenerative diseases with cancer, viral infections, and type 2 diabetes.Translational neurodegeneration · 2025Review
- Article
- Subcellular localization of SARS-CoV-2 E and 3a proteins along the secretory pathway.Journal of molecular histology · 2025Article
- Review of organ damage from COVID and Long COVID: a disease with a spectrum of pathology.Medical review (2021) · 2025Review
- Is Autophagy a Friend or Foe in SARS-CoV-2 Infection?Viruses · 2024Review
- Neurotropic virus infection and neurodegenerative diseases: Potential roles of autophagy pathway.CNS neuroscience & therapeutics · 2024Review
- Targeting the High-Density Lipoprotein Proteome for the Treatment of Post-Acute Sequelae of SARS-CoV-2.International journal of molecular sciences · 2024Article
- Regulation of Autophagosome-Lysosome Fusion by Human Viral Infections.Pathogens (Basel, Switzerland) · 2024Review
- Review
- The relationship between autophagy and respiratory viruses.Archives of microbiology · 2024Review
- SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects.Pathogens (Basel, Switzerland) · 2024Review
- Article
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes injury to multiple organ systems, including the brain. SARS-CoV-2's neuropathological mechanisms may include systemic inflammation and hypoxia, as well as direct cell damage resulting from viral infections of neurons and glia. How the virus directly causes injury to brain cells, acutely and over the long term, is not well understood. In order to gain insight into this process, we studied the neuropathological effects of open reading frame 3a (ORF3a), a SARS-CoV-2 accessory protein that is a key pathological factor of the virus. Forced ORF3a brain expression in mice caused the rapid onset of neurological impairment, neurodegeneration, and neuroinflammation-key neuropathological features found in coronavirus disease (COVID-19, which is caused by SARS-CoV-2 infection). Furthermore, ORF3a expression blocked autophagy progression in the brain and caused the neuronal accumulation of α-synuclein and glycosphingolipids, all of which are linked to neurodegenerative disease. Studies with ORF3-expressing HeLa cells confirmed that ORF3a disrupted the autophagy-lysosomal pathway and blocked glycosphingolipid degradation, resulting in their accumulation. These findings indicate that, in the event of neuroinvasion by SARS-CoV-2, ORF3a expression in brain cells may drive neuropathogenesis and be an important mediator of both short- and long-term neurological manifestations of COVID-19.
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