Biology subjects

aSCENT-PD Investigators,

Publications and source records attributed to aSCENT-PD Investigators,.

3 recordsLinked to original sources

bioRxiv2025

Elevated brain α-synuclein, phosphorylated-tau, and oxidative stress in mice that survived influenza A pneumonitis

Background: Influenza virus exposure elevates the incidence of parkinsonism. We and others previously discovered that allelic variants at the Parkinson's-linked LRRK2 locus modulate host responses to virulent microbes. Objective: We asked whether Lrrk2 mutations modify disease outcomes in adult animals following a nasally acquired lung infection. Methods: We inoculated C57BL/6J mice of mutant knock-in Lrrk2 genotypes with influenza A virus, H1N1-serotype (1 x LD 50 = 2,000 plaque-forming units). Results: During H1N1-induced pneumonitis neither homozygous nor heterozygous mutations of kinase activity-increasing Lrrk2G2019S or kinase-dead Lrrk2D1994S altered the course of sickness in mice when compared to wild-type littermates, as determined by survival rates, viral titres and weight changes in both sexes. However, six weeks after inoculation brains of H1N1-exposed, homozygous Lrrk2 p.G2019S animals showed higher pSer129 -synuclein and pSer199 tau levels than mock-treated, mutant mice (P<0.01). The ratios of phosphorylated tau-to-total tau and phosphorylated -synuclein-to-total -synuclein also rose in H1N1-exposed Lrrk2 p.G2019S mice (P<0.05). Further, we found that nitrotyrosination of the brain proteome was significantly increased in Lrrk2G2019S survivors vs. mock-exposed littermates (P<0.05). Brain H2O2 concentrations were elevated in male, H1N1-inoculated wild-type animals (with a trend seen in females and Lrrk2G2019S mice), an effect that was abrogated in kinase-dead Lrrk2D1994S mice. Conclusion: Homozygous Lrrk2G2019S-mutant mice that survived infection by a life-threatening, pneumotropic RNA virus show changes in brain levels of oxidative stress, pSer199 tau and pSer129 -synuclein. These results could be of relevance to the initiation of neurodegeneration-linked changes in humans and may help explain differences in the penetrance rate and expressivity of LRRK2 mutants.

neuroscience↗

bioRxiv2024

A Protocol for Neuralized Murine Olfactory Organoids

Chronic olfactory dysfunction can be associated with parkinsonism, dementia, demyelinating disorders and schizophrenia. The olfactory epithelium (OE) represents an interface between the environment and the central nervous system. Mounting evidence implicates environmental factors in neurodegenerative disease processes, necessitating investigations into their interactions with the hosts genome. In Parkinson disease, hyposmia often precedes motor symptoms, raising the possibility that the OE could be involved in disease initiation. We previously demonstrated abundant -synuclein expression in mammalian OE as well as aggregate formation in the olfactory nerve. Current in vitro models of OE are limited, relying primarily on post-mitotic cultures established from biopsies. To address this gap, we present a method for generating olfactory organoids of OE from adult mice. These organoids comprise neuronal and non-neuronal cell types, including sustentacular cells, thus encompassing structural elements of OE in situ. Expression of the olfactory sensory neuron marker OMP and Parkinsons-linked -synuclein was also detected in olfactory organoids, highlighting their potential usefulness to mechanistic research. We established OE organoids that were kept in culture for up to 3 weeks. In addition, we inoculated organoids with the neurotropic vesicular stomatitis virus to model infections. We conclude that this olfactory organoid model system offers a new platform for studying airborne environmental factors in their interactions with a genetically defined host; this, to study OE biology and enable the exploration of disease processes within olfactory tissue.

neuroscience↗

bioRxiv2023

Neuropathological assessment of the olfactory bulb and tract in individuals with COVID-19

The majority of patients with Parkinson disease (PD) experience a loss in their sense of smell and accumulate insoluble -synuclein aggregates in their olfactory bulbs (OB). Subjects affected by a SARS-CoV-2-linked illness (COVID-19) frequently experience hyposmia. We previously hypothesized that -synuclein and tau misprocessing could occur following host responses to microbial triggers. Using semiquantitative measurements of immunohistochemical signals, we examined OB and olfactory tract specimens collected serially at autopsies between 2020 and 2023. Deceased subjects comprised 50 adults, which included COVID19+ patients (n=22), individuals with Lewy body disease (e.g., PD and dementia with Lewy bodies (DLB; n=6)), Alzheimer disease (AD; n=3), other non-synucleinopathy-linked degenerative diseases (e.g., progressive supranuclear palsy (PSP; n=2) and multisystem atrophy (MSA; n=1)). Further, we included neurologically healthy controls (HCO; n=9) and those with an inflammation-rich brain disorder as neurological controls (NCO; n=7). When probing for inflammatory changes focusing on anterior olfactory nuclei (AON) using anti-CD68 immunostaining, scores were consistently elevated in NCO and AD cases. In contrast, inflammation on average was not significantly altered in COVID19+ patients relative to controls, although anti-CD68 reactivity in their OB and tracts declined with progression in age. Mild-to-moderate increases in phospho-Syn and phospho-tau signals were detected in the AON of tauopathy-and synucleinopathy-afflicted brains, respectively, consistent with mixed pathology, as described by others. Lastly, when both sides were available for comparison in our case series, we saw no asymmetry in the degree of pathology of the left versus right OB and tracts. We concluded from our autopsy series that after a fatal course of COVID-19, microscopic changes -when present-in the rostral, intracranial portion of the olfactory circuitry generally reflected neurodegenerative processes seen elsewhere in the brain. In general, inflammation correlated best with the degree of Alzheimers-linked tauopathy and declined with progression of age in COVID19+ patients.

pathology↗