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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