Biology subjects

Smeyne, R. J.

Publications and source records attributed to Smeyne, R. J..

4 recordsLinked to original sources

bioRxiv2024

Environmental exposures and familial background alter the induction of neuropathology and inflammation after SARS-CoV-2 infection.

AbstractBasal ganglia disease has been reported as a post-infection sequela of several viruses, with documentation of this phenomenon from the H1N1 Spanish flu to the recent COVID-19 (SARS-CoV-2) pandemic. SARS-CoV-2 infection leads to multisystem deficits, including those affecting the nervous system. Here, we investigated whether a SARS-CoV-2 infection alone increases the susceptibility to develop parkinsonian phenotypes in C57BL/6J mice expressing the human ACE2 receptor, or in addition to two well-known toxin exposures, MPTP and paraquat. Additionally, we examined mice carrying a G2019S mutation in the LRRK2 gene. We also examined if vaccination with either an mRNA- or protein-based vaccine can alter any observed neuropathology. We find that the infection with the WA-1/2020 (alpha) or omicron B1.1.529 strains in ACE2 and G2019S LRRK2 mice both synergize with a subtoxic exposure to the mitochondrial toxin MPTP to induce neurodegeneration and neuroinflammation in the substantia nigra. This synergy appears toxin-dependent since we do not observe this following exposure to the direct redox-inducing compound paraquat. This synergistic neurodegeneration and neuroinflammation is rescued in WT mice that were vaccinated using either mRNA- and protein- based vaccines directed against the Spike protein of the SARS-CoV-2 virus. However, in the G2019S LRRK2 mutant mice, we find that only the protein-based vaccine but not the mRNA- based vaccine resulted in a rescue of the SARS-CoV-2 mediated neuropathology. Taken together, our results highlight the role of both environmental exposures and familial background on the development of parkinsonian pathology secondary to viral infection and the benefit of vaccines in reducing these risks.

neuroscience↗

bioRxiv2024

Templating of Monomeric Alpha-Synuclein Induces Inflammation and SNpc Dopamine Neuron Death in a Genetic Mouse Model of Synucleinopathy.

While the etiology of most cases of Parkinsons disease (PD) are idiopathic, it has been estimated that 5-10% of PD arise from known genetic mutations. The first mutations described that leads to the development of an autosomal dominant form of PD are in the SNCA gene that codes for the protein alpha-synuclein (-syn). -syn is an abundant presynaptic protein that is natively disordered and whose function is still unclear. In PD, -syn misfolds into multimeric {beta}-pleated sheets that aggregate in neurons (Lewy Bodies/neurites) and spread throughout the neuraxis in a pattern that aligns with disease progression. Here, using IHC, HPLC, and cytokine analysis, we examined the sequelae of intraparenchymal brain seeding of oligomeric pre-formed fibrils (PFFs) and monomeric -syn in C57BL/6J (WT) and A53T SNCA mutant mice. We found that injection of PFFs, but not monomeric -syn, into the striatum of C57BL/6J mice induced spread of aggregated -syn, loss of SNpc DA neurons and increased neuroinflammation However, in A53T SNCA mice, we found that both PFFs and monomeric -syn induced this pathology. This suggests that the conformation changes in -syn seen in the A53T strain can recruit wild-type -syn to a pathological misfolded conformation which may provide a mechanism for the induction of PD in humans with SNCA duplication/triplication.

neuroscience↗

bioRxiv2022

Neurobiological and Behavioral Characterization of Adult Male and Female Mice in Prolonged Social Isolation

As social animals, our health depends in part on interactions with other human beings. Yet millions suffer from chronic social isolation, including those in nursing/assisted living facilities and people experiencing chronic loneliness. Perhaps the most egregious form of chronic isolation is seen in criminal justice system, where approximately 80,000 people are housed, on any one day, in solitary confinement. In this study, we developed a model of isolation that starts in adulthood. Mice (C57BL/6J) were born and raised in an enriched environment until 4 months of age and then either maintained in that environment or moved to social isolation for 1 or 3 months. We then examined neuronal structure, catecholamine and brain derived neurotrophic factor (BDNF) levels, and CNS-mediated behaviors, comparing social isolation to enriched environment controls. We found there were significant changes in neuronal volume, dendritic length, neuronal complexity, and spine density that were dependent on brain region, sex, and duration of the isolation. Isolation altered dopamine in the striatum and serotonin levels in the forebrain in a sex-dependent manner, and also reduced levels of BDNF in the motor cortex and hippocampus of male but not female mice. To determine if SI altered a behavior, we tested mice in the open-field (general activity), the resident intruder paradigm (aggression), the tail suspension test (depression), and the Barnes maze (spatial memory). Adult male mice isolated for 1 month exhibited increased locomotor activity, aggression, and enhanced aspects of spatial memory, most of which remained after 3 months of isolation. After 3 months of isolation, mice also exhibited depressive behaviors. Similar (but not exact) results were seen in female mice, with the exception that the females did not show increased aggression. These studies show that isolation enforced in adulthood has significant impact on brain structure, neurochemistry, and behavior.

neuroscience↗

bioRxiv2022

COVID-19 infection enhances susceptibility to oxidative-stress induced parkinsonism

BackgroundViral induction of neurological syndromes has been a concern since parkinsonian-like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses following SARS-CoV-2 infection with those observed after pandemic influenza, there is a question if a similar syndrome of post-encephalic parkinsonism could follow COVID-19 infection. ObjectivesTo determine if prior infection with SARS-CoV-2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism. MethodshACE2 mice were infected with SARS-CoV-2 to induce mild to moderate disease. After 31 days recovery, mice were administered a non-lesion inducing dose of the parkinsonian toxin MPTP. Subsequent neuroinflammation and SNpc dopaminergic neuron loss was determined and compared to SARS-CoV-2 or MPTP alone. ResultshACE2 mice infected with SARS-CoV-2 or MPTP showed no SNpc DA neuron loss following MPTP. In mice infected and recovered from SARS-CoV-2 infection, MPTP induced a 23% or 19% greater loss of SNpc dopaminergic neurons than SARS-CoV-2 or MPTP, respectively (p{square}<{square}0.05). Examination of microglial activation showed a significant increase in the number of activated microglia in the SARS-CoV-2 + MPTP group compared to SARS-CoV-2 or MPTP alone. ConclusionsOur observations have important implications for long-term public health, given the number of people that have survived SARS-CoV-2 infection as well as for future public policy regarding infection mitigation. However, it will be critical to determine if other agents known to increase risk of PD also have synergistic effects with SARS-CoV-2 and if are abrogated by vaccination. FundingThis work was supported by grant from the State of North Carolina (PS, JE, DOR, RJS) and R21 NS122280 (RJS).

neuroscience↗