Biology subjects

Steiner, J. A.

Publications and source records attributed to Steiner, J. A..

7 recordsLinked to original sources

bioRxiv2026

Neuroinflammation is an early pathological process in a mouse model of prodromal Parkinsons disease

Approximately 90% of Parkinson's disease (PD) patients exhibit olfactory deficits, which often precedes motor symptoms by years, and are a robust predictor for PD and subsequent cognitive decline. Pathological changes in the PD olfactory system, particularly synuclein (Syn) pathology in the olfactory bulb (OB) and severe involvement of the anterior olfactory nucleus (AON), are distinct from normal aging. However, the causal link between Syn aggregation and functional impairment, potentially involving cytotoxicity and neuroinflammation, remains elusive. To investigate these early pathological events, we utilized a prodromal PD model that we have previously characterized, involving the unilateral OB injection of Syn preformed fibrils (PFF) in wild-type mice. This triggers the transneuronal spread of pathogenic Syn, and olfactory dysfunction starting at 1-month post-injections. Here we report on neuropathological and inflammatory events 1-3 month following injection of PFFs into the OB. Following PFF injection, Syn pSer129 pathology progressively accumulated bilaterally in the AON and ipsilateral in the piriform cortex (PCX) over three months. Stereological quantification revealed no significant neuronal loss in the AON or PCX during this 1-3 month interval, indicating that olfactory impairment precedes overt neurodegeneration. Instead, we identified the upregulation of pro-inflammatory genes (Il-1{beta} ; and Il-6), significant microglial reactivity, and sustained astrogliosis within olfactory structures. These findings identify neuroinflammation as a key early mediator linking Syn pathology to olfactory dysfunction in the absence of neuronal loss. This suggests a critical window for therapeutic intervention and highlights neuroinflammatory markers as potential biomarkers for the prodromal phase of PD.

neuroscience↗

bioRxiv2025

Whole-genome DNA methylation profiling in COVID-19 positive patients reveals alterations in pathways linked to neurological dysfunction

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible RNA betacoronavirus, causing coronavirus disease-19 (COVID-19). Infection with SARS-CoV-2 can result in a broad spectrum of clinical outcomes, ranging from asymptomatic or mild to a severe, deadly illness. Emerging evidence suggests SARS-CoV-2 affects host gene regulation through epigenetic mechanisms, such as DNA methylation, potentially contributing to immune dysregulation and post-acute sequelae, including neurological and psychiatric disorders. However, the extent and functional relevance of these epigenetic changes remain uncertain. Methods and resultsWe employed whole-genome bisulfite sequencing to profile DNA methylation in peripheral blood from SARS-CoV-2-positive patients across a spectrum of symptom severity, ranging from asymptomatic to severe (n=101), in comparison to SARS-CoV-2-negative individuals (n=105). We observed a widespread hypomethylation in the genomes of infected individuals, which was more pronounced in severe cases. Notably, we identified differentially methylated genes in patients with mild (19 genes), moderate (19 genes), and severe (35 genes) symptoms. These genes included those involved in canonical immune responses as well as known to be linked to neurodegenerative diseases. Subsequent pathway enrichment analysis further supported the significant association between the differentially methylated genes and those implicated in Alzheimers and Parkinsons disease, as well as neuropsychiatric conditions, suggesting potential epigenetic links between acute SARS-CoV-2 infection and long-term neurological outcomes. This is one of the first studies to comprehensively map severity-stratified genome-wide DNA methylation changes in COVID-19 patients. ConclusionOur findings underscore the potential importance of epigenetic regulation in the acute responses to SARS-CoV-2 infection and highlight an overlap with epigenetic mechanisms relevant for neuropsychiatric disease processes.

neuroscience↗

bioRxiv2024

Tet2 loss suppress α-synuclein pathology by stimulating ciliogenesis

There are no approved treatments that slow Parkinsons disease (PD) progression and therefore it is important to identify novel pathogenic mechanisms that can be targeted. Loss of the epigenetic marker, Tet2 appears to have some beneficial effects in PD models, but the underlying mechanism of action is not well understood. We performed an unbiased transcriptomic analysis of cortical neurons isolated from patients with PD to identify dysregulated pathways and determine their potential contributions to the disease process. We discovered that genes associated with primary cilia, non-synaptic sensory and signaling organelles, are upregulated in both early and late PD patients. Enhancing ciliogenesis in primary cortical neurons via sonic hedgehog signaling suppressed the accumulation of -synuclein pathology in vitro. Interestingly, deletion of Tet2 in mice also enhanced the expression of primary cilia and sonic hedgehog signaling genes and rescued the accumulation of -synuclein pathology and dopamine neuron degeneration in vivo. Our findings demonstrate the crucial role of Tet2 loss in regulating ciliogenesis and potentially affecting the progression of PD pathology.

neuroscience↗

bioRxiv2022

Synaptic Location Is a Determinant of the Detrimental Effects of α-Synuclein Pathology to Glutamatergic Transmission in the Basolateral Amygdala

The presynaptic protein -synuclein (Syn) has been suggested to be involved in the pathogenesis of Parkinsons disease (PD). In PD, the amygdala is prone to develop insoluble Syn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how Syn aggregates affect amygdala function is unknown. In this study, we examined Syn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that Syn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1+) terminals in mouse BLA, which is consistent with higher levels of Syn expression in vGluT1+ glutamatergic neurons in the cerebral cortex relative to the vGluT2+ glutamatergic neurons in the thalamus. We found that Syn aggregation selectively decreased the cortico-BLA, but not the thalamo-BLA, transmission; and that cortico-BLA synapses displayed enhanced short-term depression upon repetitive stimulation. In addition, using confocal microscopy, we found that vGluT1+ axon terminals exhibited decreased levels of soluble Syn, which suggests that lower levels of soluble Syn might underlie the enhanced short-term depression of cortico-BLA synapses. In agreement with this idea, we found that cortico-BLA synaptic depression was also enhanced in Syn knockout mice. In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of Syn and these changes might be relevant to the perturbed cortical control of the amygdala that has been suggested to play a role in psychiatric symptoms in PD.

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bioRxiv2020

α-Synuclein perturbs in vivo neural activity following seeding in the olfactory bulb

BACKGROUNDParkinsons disease (PD) neuropathology is characterized by intraneuronal protein aggregates composed of misfolded -Synuclein (-Syn), as well as degeneration of substantia nigra dopamine neurons. Deficits in olfactory perception and aggregation of -Syn in the olfactory bulb (OB) are observed during early stages of PD, and have been associated with the PD prodrome, before onset of the classic motor deficits. -Syn fibrils injected into the OB of mice cause progressive propagation of -Syn pathology throughout the olfactory system and are coupled to olfactory perceptual deficits. OBJECTIVEWe hypothesized that accumulation of pathogenic -Syn in the OB impairs neural activity in the olfactory system. METHODSTo address this, we monitored spontaneous and odor-evoked local field potential dynamics in awake wild type mice simultaneously in the OB and piriform cortex (PCX) one, two, and three months following injection of pathogenic preformed -Syn fibrils in the OB. RESULTSWe detected -Syn pathology in both the OB and PCX. We also observed that -Syn fibril injections influenced odor-evoked activity in the OB. In particular, -Syn fibril-injected mice displayed aberrantly high odor-evoked power in the beta spectral range. A similar change in activity was not detected in the PCX, despite high levels of -Syn pathology. CONCLUSIONSTogether, this work provides evidence that synucleinopathy impacts in vivo neural activity in the olfactory system at the network-level.

neuroscience↗

bioRxiv2019

Loss of one Engrailed1 allele enhances induced α-synucleinopathy

BackgroundParkinsons disease (PD) is a synucleinopathy that has multiple neuropathological characteristics, with nigrostriatal dopamine system degeneration being a core feature. Current models of PD pathology typically fail to recapitulate several attributes of the pathogenic process and neuropathology. We aimed to define the effects of combining a mouse model exhibiting multiple PD-like changes with intrastriatal injections of -synuclein (-syn) pre-formed fibrils (PFFs) aggregates. We employed the heterozygous Engrailed 1 (En1+/-) mouse that features several pathophysiological hallmarks of clinical PD. Objective: To test the hypothesis that the neuropathological changes in the En1+/- mice will promote formation of -syn aggregates following intrastriatal injections of pathogenic human -syn PFFs. Methods: We unilaterally injected PFFs into the striata of 1 month-old En1+/- and control wild-type mice and euthanized animals at 3 months for post-mortem analysis. Results: Using immunohistochemistry and unbiased stereology, we established that PFF-injected En1+/- mice exhibited a near-threefold increase in pS129--syn-positive neurons in the substantia nigra compared to PFF-injected wild-type mice. The PFF-injected En1+/- mice also displayed significant increases in pS129--syn-positive neurons in the amygdala and ventral tegmental area; regions of known PD pathology with projections to the striatum. Additionally, we observed amplified pS129--syn-positive aggregation in En1+/- mice in multiple cortical regions. Conclusions: Following intrastriatal injection of PFFs, absence of an En1 allele leads to additional aggregation of pathological -syn, potentially due to En1-loss mediated nigrostriatal impairment. We propose that further development of this double-hit model could be predictive of pre-clinical therapeutic potential and success for PD than existing mouse models.

neuroscience↗

bioRxiv2018

Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology

Intraneuronal accumulation of -synuclein (Syn) is key in the pathogenesis of Parkinsons disease (PD). Published studies suggest that this process begins in the enteric nervous system (ENS) and propagates into the brain decades before clinical diagnosis of PD. The triggers and mechanisms underlying the accumulation of Syn remain unknown but evidence is growing, that immune pathways and in particular colitis may play a critical role. Here we demonstrate that patients with inflammatory bowel disease (IBD) exhibit Syn accumulation in their colon. We then confirmed in an experimental model of IBD that intestinal inflammation can trigger Syn accumulation in the ENS of wildtype and Syn transgenic mice. We discovered that the type and degree of inflammation modulates the extent of Syn accumulation in the colon and that macrophage-related signaling limits this process. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 Syn in the midbrain, including the substantia nigra, in 21-month but not 9-month-old Syn transgenic mice. This was accompanied by loss of nigral tyrosine hydroxylase-immunoreactive neurons, another neuropathological hallmark of PD. Together, our data suggest a critical role for intestinal inflammation in the initiation and progression of PD.

neuroscience↗