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 pathoge...