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Principal Investigator: Xiaohong Lu
Organization: LOUISIANA STATE UNIV HSC SHREVEPORT
Fiscal Year: 2024
Award: $506,052
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary/Abstract
Neuropathological interactions between COVID-19 and ADRD suggest shared molecular and cellular
mechanisms. A recent case series study revealed striking cutaneous Lewy pathology (phosphorylated α-
synuclein) in Long-COVID Postural orthostatic tachycardia syndrome (POTS) patients. Animal studies
consistently show that viral infection can trigger α-synucleinopathies in hamster and macaque SARS-CoV-2
infection models. SARS-CoV-2 N-and Spike protein can bind to α-Synuclein to induce Lewy pathology in vitro.
Recent human single-neuron sequencing findings of accumulation of non-germline inherited somatic mutations
associated with neurodegenerative disorders support the pathogenic role of genotoxic stress in age-dependent
long-lasting neurologic deficits and cognitive decline. These observations support the role of infection in the
pathogenesis of synucleinopathy, a pathological intracellular proteinaceous α-Synuclein (α-Syn) inclusions that
are characteristic of neurological disorders, including dementia with Lewy body (DLB), LB variant of Alzheimer's
disease (LBVAD), PD, NBIA-1, and MSA, with DLB being the second most common type of dementia after AD.
Ours and other studies have begun to reveal the role of genotoxic stress interplaying with autophagy-lysosome
function in synucleinopathy. To study the impact of virus infection on synucleinopathy in vivo, we created a
human ACE2 transgenic mouse model with full-length human ACE2 regulatory regions that faithfully
recapitulated the structure, tissue distribution, and gene regulation of the human gene. A strategy was developed
to model the robust immunopathology of SARS-CoV-2 infection to facilitate the longitudinal analysis in an ABSL-
2 facility. Two months after the virus infection, mice demonstrated cognitive deficits, anosmia, and
neuroinflammation, recapitulating clinical features in long COVID patients and, surprisingly, with Lewy pathology.
Inhibiting genotoxic stress can effectively lessen inflammation, cell senescence, accumulation of α-Synuclein,
autophagy deficits, neuroinflammation, and PASC-like symptoms. We hypothesize viral inflammation-inflicted
genotoxic stress interacts with autophagy/lysosome pathway to precipitate Lewy pathology and drives chronic
neurocognitive and neurological deficits. Aim 1 will determine if virus infection-inflicted genotoxic stress can
accelerate the progression of Lewy pathology and cognitive deficits in a mouse model of LBD. Aim 2 will trace
the temporal and spatial progression of viral infection-driven olfactory spreading of Lewy pathology and genotoxic
stress and autophagy-lysosome dysfunction with a novel genetic sensor. Aim 3 will dissect the causal pathogenic
role of virus-inflicted genotoxic stress in Lewy pathology and olfactory and cognitive deficits via pharmacologic
and a novel "seek and rescue" genetic intervention. This project promises novel animal models, tools,
approaches, and mechanistic studies of the converging pathogenic cross-talking of genotoxic stress with
autophagy-lysosome pathways in mediating the neuropathologic interaction of virus infection and dementia. The
findings will transform the current paradigm of the viral origin of neurodegeneration and advance the therapeutic
targeting of genotoxic stress for PASCs, Lewy pathology, and dementia.
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Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><AD dementia><AD pathology><AD related dementia><ADRD><ARDS><Acceleration><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease pathology><Alzheimer's disease related dementia><Alzheimer's pathology><Alzheimers Dementia><Amentia><Anatomic Sites><Anatomic structures><Anatomy><Animal Model><Animal Models and Related Studies><Animals><Anosmia><Assay><Autophagocytosis><BSL-2 facility><BSL2 facility><Behavioral><Binding><Bioassay><Biological Assay><Brain><Brain Nervous System><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 predisposition><COVID-19 public health crisis><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 susceptibility><COVID-19 virus><COVID-19 virus infection><COVID-19 vulnerability><COVID-19 years><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><Case Series><Causality><Cell Aging><Cell Body><Cell Senescence><Cells><Cellular Aging><Cellular Senescence><Cellular Stress><Cellular Stress Response><Cellular injury><Cessation of life><Characteristics><Chronic><Chronic Fatigue Disorder><Chronic Fatigue Syndrome><Chronic Fatigue and Immune Dysfunction Syndrome><Chronic Infectious Mononucleosis-Like Syndrome><Clinical><CoV-2><CoV2><Cognitive Disturbance><Cognitive Impairment><Cognitive Manifestations><Cognitive Symptoms><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Coronavirus Infectious Disease 2019><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Cricetinae><Cutaneous><DNA Damage><DNA Injury><DNA Therapy><Da Nang Lung><Data><Death><Degenerative Neurologic Disorders><Dementia><Dementia with Lewy Bodies><Dissection><Disturbance in cognition><Drug or chemical Tissue Distribution><Drugs><Dysautonomia-Orthostatic Hypotension Syndrome><Dysautonomic Orthostatic Hypotension><Dysfunction><Encephalon><Etiology><Functional disorder><Gene Action Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transfer Clinical><Genes><Genetic><Genetic Intervention><Genetic Technics><Genetic Techniques><Genotoxic Stress><Gulf War Illness><Gulf War Syndrome><Hallervorden-Spatz Disease><Hallervorden-Spatz Syndrome><Hamsters><Hamsters Mammals><Hereditary><Heterozygote><Hospital Admission><Hospitalization><Human><Huntington Chorea><Huntington Disease><Huntington's><Huntington's Disease><Huntingtons Disease><IQ Deficit><Impaired cognition><In Vitro><Individual><Infection><Inflammation><Inherited><Injections><Intervention><Intervention Strategies><Investigation><LB dementia><LB pathology><Length><Lewy Bodies><Lewy Body Dementia><Lewy Body Type Senile Dementia><Lewy body pathology><Lewy dementia><Lewy pathology><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Lysosomes><ME/CFS><Macaca><Macaque><Mediating><Medication><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Multiple System Atrophy><Multiple System Atrophy Syndrome><Multisystem Atrophy><Multisystemic Atrophy><Murine><Mus><Myalgic Encephalomyelitis><NAC precursor><NBIA><Nature><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurobehavioral Manifestations><Neurobehavioral Signs and Symptoms><Neurocognitive Deficit><Neurocyte><Neurodegeneration with brain iron accumulation><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic><Neurologic Deficit><Neurologic Degenerative Conditions><Neurologic Disorders><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological><Neurological Disorders><Neurological Manifestations><Neurological Signs and Symptoms><Neuron Degeneration><Neurons><Nucleic Acid Regulator Regions><Nucleic Acid Regulatory Sequences><PARK1 protein><PARK4 protein><PASC><Paralysis Agitans><Parkinson><Parkinson Disease><Pathogenesis><Pathogenicity><Pathologic><Pathology><Pathway interactions><Patients><Persian Gulf Syndrome><Pharmaceutical Preparations><Phosphorylation><Physiopathology><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Postural Orthostatic Tachycardia Syndrome><Postural Tachycardia Syndrome><Postviral Fatigue Syndrome><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Primary Parkinsonism><Primary Senile Degenerative Dementia><Progressive Autonomic Failure><Protein Phosphorylation><Proteins><Regulatory Regions><Replicative Senescence><Reporter><Research><Resolution><Risk><Role><Royal Free Disease><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 predisposition><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 susceptibility><SARS-CoV-2 vulnerability><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SNCA><SNCA protein><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vulnerability><Severe acute respiratory syndrome related corona virus 2><Severities><Shock Lung><Shy-Drager Syndrome><Shy-Drager Type Idiopathic Orthostatic Hypotension><Somatic Mutation><Stiff lung><Structure><Symptoms><Tissue Distribution><Transgenic Mice><Variant><Variation><Viral><Viral Diseases><Viral Pathogenesis><Virus><Virus Diseases><Visualization><Wuhan coronavirus><a-syn><a-synuclein><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><age associated><age correlated><age dependent><age linked><age related><age specific><aged brain><aging brain><alpha synuclein><alpha synuclein gene><alphaSP22><analyzing longitudinal><angiotensin converting enzyme 2><angiotensin converting enzyme II><animal imaging><anosphrasia><associated symptom><asyn><autophagy><biosafety level 2 facility><causation><cell damage><cell injury><cell stress><cellular damage><chemobrain><chemotherapy-induced cognitive impairment><chemotherapy-related cognitive impairment><chronic COVID><chronic COVID-19><chronic COVID-19 sequelae><chronic novel coronavirus disease 2019><co-morbid symptom><co-occuring symptom><cognitive defects><cognitive dysfunction><cognitive loss><comorbid symptom><concurrent symptom><cooccuring symptom><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine release syndrome><cytokine storm><damage to cells><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><disease causation><drug/agent><experience><gene repair therapy><gene therapy><gene-based therapy><genetic approach><genetic regulatory element><genetic strategy><genetic therapy><genomic therapy><hCoV19><heterozygosity><immunopathology><in vivo><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><injury to cells><innovate><innovation><innovative><insight><intelligence quotient deficit><interventional strategy><late infantile Neuroaxonal dystrophy><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><longitudinal analysis><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><loss of smell><model of animal><molecular biomarker><molecular marker><mouse model><murine model><mutant mouse model><nCoV2><neural degeneration><neural inflammation><neural manifestation><neurobehavioral symptom><neurocognitive decline><neurocognitive impairment><neurodegeneration><neurodegenerative><neurodegenerative illness><neuroinflammation><neuroinflammatory><neurological degeneration><neurological disease><neuronal><neuronal degeneration><neuropathologic><neuropathological><neuropathology><non A-beta component of AD amyloid><non A4 component of amyloid precursor><novel><olfactory bulb><olfactory loss><pathophysiology><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><persistent COVID-19><pharmacologic><post COVID syndrome><post COVID-19 sequelae><post COVID-19 syndrome><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute sequelae following COVID-19><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-acute phases of COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><post-chemotherapy cognitive impairment><post-orthostatic tachycardia><postural orthostatic tachycardia><predisposed to Coronavirus disease 2019><primary degenerative dementia><prolonged COVID-19 symptoms><resolutions><response><senescence><senescent><senile dementia of the Alzheimer type><sensor><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><small molecule><social role><somatic variant><spike proteins on SARS-CoV-2><susceptible to COVID-19><susceptible to Coronavirus disease 2019><susceptible to SARS-CoV-2><susceptible to Severe acute respiratory syndrome coronavirus 2><symptom association><symptom comorbidity><symptomatology><synucleinopathy><systemic inflammation><systemic inflammatory response><therapeutic target><tool><viral infection><virus infection><virus pathogenesis><virus-induced disease><vulnerable to COVID-19><vulnerable to Coronavirus disease 2019><vulnerable to SARS-CoV-2><vulnerable to Severe acute respiratory syndrome coronavirus 2><wet lung><α synuclein gene><α-syn><α-synuclein>