Document text
Principal Investigator: Richard Proia
Organization: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Fiscal Year: 2024
Award: $3,503,685
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes injury to multiple organ systems, including the brain. SARS-CoV-2s 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). Further, ORF3a expression blocked autophagy progression in the brain and caused the neuronal accumulation of alpha-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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acute><Asialogangliosides><Autophagocytosis><Biology><Body System><Brain><Brain Nervous System><COVID-19><COVID-19 infection><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><CV-19><Cell Communication and Signaling><Cell Function><Cell Membrane Structures><Cell Physiology><Cell Process><Cell Signaling><Cellular Function><Cellular Physiology><Cellular Process><Cellular injury><CoV disease><CoV-2><CoV2><Complex><Coronavirus Infectious Disease 2019><DNA Alteration><DNA Sequence><DNA Sequence Alteration><DNA Therapy><DNA mutation><Degenerative Neurologic Disorders><Disease><Disorder><Encephalon><Event><Frontal Temporal Dementia><Frontotemporal Dementia><Gaucher Disease><Gauchers Disease><Gene Transfer Clinical><Genetic Intervention><Genetic mutation><Glia><Glial Cells><Glycosphingolipids><Goals><HeLa><Hela Cells><Hexosaminidase A Deficiency Disease><Hypoxia><Hypoxic><Impairment><Injury><Intermediary Metabolism><Intracellular Communication and Signaling><Kolliker's reticulum><Link><Lipids><Lysosomal Enzyme Disorders><Lysosomal Storage Diseases><Mediator><Membrane Structure and Function><Metabolic Processes><Metabolism><Mice><Mice Mammals><Murine><Mus><NAC precursor><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neuroglia><Neuroglial Cells><Neurologic><Neurologic Body System><Neurologic Degenerative Conditions><Neurologic Manifestations><Neurologic Organ System><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological><Neurological Manifestations><Neurological Signs and Symptoms><Neuron Degeneration><Neurons><Neuropathogenesis><Non-neuronal cell><Nonneuronal cell><ORFs><Open Reading Frames><Organ System><Oxygen Deficiency><PARK1 protein><PARK4 protein><Paralysis Agitans><Parkinson><Parkinson Disease><Pathologic><Pathway interactions><Play><Primary Parkinsonism><Process><Protein Coding Region><Proteins><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SNCA><SNCA protein><Sequence Alteration><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Sphingoglycolipids><Sphingolipids><Subcellular Process><Tay-Sachs Disease><Type I GM2 Gangliosidosis><Viral Diseases><Virus><Virus Diseases><Wuhan coronavirus><a-syn><a-synuclein><age associated neurodegeneration><age associated neurodegenerative disease><age associated neurodegenerative disorder><age dependent neurodegeneration><age dependent neurodegenerative condition><age dependent neurodegenerative disease><age dependent neurodegenerative disorder><age related neurodegeneration><age-driven neurodegenerative disorders><age-related neurodegenerative disease><age-related neurodegenerative disorder><aging associated neurodegeneration><aging associated neurodegenerative disease><aging related neurodegeneration><aging related neurodegenerative disease><aging related neurodegenerative disorder><alpha synuclein><alpha synuclein gene><alphaSP22><asyn><autophagy><biological signal transduction><brain cell><cell damage><cell injury><cellular damage><corona virus disease><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><damage to cells><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><develop therapy><disease model><disorder model><front temporal dementia><frontal lobe dementia><frontotemporal lobar dementia><frontotemporal lobe degeneration associated with dementia><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic alteration><genomic therapy><hCoV19><hexosaminidase A deficiency><inborn lysosomal enzyme disorder><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><injuries><injury to cells><insight><intervention development><lysosomal disease><lysosomal disorder><lysosome storage diseases><mouse model><murine model><mutation correction><nCoV2><nerve cement><neural degeneration><neural inflammation><neural manifestation><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal><neuronal degeneration><neuropathologic><neuropathological><neuropathology><non A-beta component of AD amyloid><non A4 component of amyloid precursor><pathway><social role><systemic inflammation><systemic inflammatory response><therapeutic target><therapy development><treatment development><viral infection><virus infection><virus-induced disease><α synuclein gene><α-syn><α-synuclein>