Biology subjects

Merchak, A. R.

Publications and source records attributed to Merchak, A. R..

5 recordsLinked to original sources

bioRxiv2024

RGS10 Attenuates Systemic Immune Dysregulation Induced by Chronic Inflammatory Stress

Regulator of G-protein signaling 10 (RGS10), a key homeostatic regulator of immune cells, has been implicated in multiple diseases associated with aging and chronic inflammation including Parkinsons Disease (PD). Interestingly, subjects with idiopathic PD display reduced levels of RGS10 in subsets of peripheral immune cells. Additionally, individuals with PD have been shown to have increased activated peripheral immune cells in cerebral spinal fluid (CSF) compared to age-matched healthy controls. However, it is unknown whether CSF-resident peripheral immune cells in individuals with PD also exhibit decreased levels of RGS10. Therefore, we performed an analysis of RGS10 levels in the proteomic database of the CSF from the Michael J. Fox Foundation Parkinsons Progression Markers Initiative (PPMI) study. We found that RGS10 levels are decreased in the CSF of individuals with PD compared to healthy controls and prodromal individuals. Moreover, we find that RGS10 levels decrease with age but not PD progression and that males have less RGS10 than females in PD. Importantly, studies have established an association between chronic systemic inflammation (CSI) and neurodegenerative diseases, such as PD, and known sources of CSI have been identified as risk factors for developing PD; however, the role of peripheral immune cell dysregulation in this process has been underexplored. As RGS10 levels are decreased in the CSF and circulating peripheral immune cells of individuals with PD, we hypothesized that RGS10 regulates peripheral immune cell responses to CSI prior to the onset of neurodegeneration. To test this, we induced CSI for 6 weeks in C57BL6/J mice and RGS10 KO mice to assess circulating and CNS-associated peripheral immune cell responses. We found that RGS10 deficiency synergizes with CSI to induce a bias for inflammatory and cytotoxic cell populations, a reduction in antigen presentation in peripheral blood immune cells, as well as in and around the brain that is most notable in males. These results highlight RGS10 as an important regulator of the systemic immune response to CSI and implicate RGS10 as a potential contributor to the development of immune dysregulation in PD.

immunology↗

bioRxiv2024

High-plex Digital Spatial Profiling Identifies Subregion-Dependent Directed Proteome Changes Across Multiple Variants of Dementia

Frontotemporal lobar degeneration (FTLD) is the leading cause of dementia in patients under the age of 65. Even in a single anatomical region, there is variance within pathological protein deposition as a result of FTLD. This spectrum of pathology leads to difficulty in identification of the disease during its progression and consequential varied post mortem clinicopathological diagnoses. NanoString GeoMx Digital Spatial Profiling (DSP) is a novel method that leverages the ability to spatially multiplex protein biomarkers of interest. We utilized NanoString DSP to investigate the proteome geography at two levels of the cortex and the subcortical white matter in patients with various types of dementia (Alzheimers disease, FTLD-c9ALS, FTLD-17, FTLD-TDP, FTLD-GRN; n=6 per syndrome) and neurologically healthy controls (NHC). Analysis of 75 different protein biomarkers of interest revealed both a disease and cortical subregion specific biomarker profile. Layers II-V of the cortex from diseased individuals displayed the greatest protein dysregulation as compared to NHC. Additionally, out of all disease groups within cortical layer 1, II-V and white matter, the FTLD-17 group had the most significant protein dysregulation as compared to NHC--specifically associated with immune cell pathways. Traditional biomarkers of dementia, such as various phosphorylated tau proteins and amyloid-{beta} 42 displayed dysregulation, however our data suggest spatial enrichment in distinct to cortical sublayers. In conclusion, we observed that depending on the variant of disease, specific protein deposits either span multiple levels of cortical geography or only a single layer. Thus, the specific localization of these deposits could potentially be used to elucidate region-specific pathologic biomarkers unique to individual variants of dementia.

neuroscience↗

bioRxiv2023

Lactobacillus maintains IFNγ homeostasis to promote behavioral stress resilience.

The gut microbiome consists of the trillions of bacteria, fungi, and viruses that inhabit the digestive tract. These communities are sensitive to disruption from environmental exposures ranging from diet changes to illness. Disruption of the community of lactic acid producing bacteria, Lactobaccillacea, has been well documented in mood disorders and stress exposure. In fact, oral supplement with many Lactobacillus species can ameliorate these effects, preventing depression- and anxiety-like behavior. Here, for the first time, we utilize a gnotobiotic mouse colonized with the Altered Schaedler Flora to remove the two native species of Lactobaccillacea. Using this novel microbial community, we found that the Lactobacillus species themselves, and not the disrupted microbial communities are protective from environmental stressors. Further, we determine that Lactobaccillacea are maintaining homeostatic IFN{gamma} levels which are mediating these behavioral and circuit level responses. By utilizing the Altered Schaedler Flora, we have gained new insight into how probiotics influence behavior and give novel methods to study potential therapies developed to treat mood disorders.

neuroscience↗

bioRxiv2022

Stress-Induced Mucosal Layer Disruption Drives Gut Dysbiosis and Depressive-like Behaviors

Depression is a prevalent psychological condition with limited treatment options. While its etiology is multifactorial, both chronic stress and changes in the microbiome are associated with disease pathology. In depression, stress is known to induce microbiome dysbiosis, defined here as a change in microbial composition associated with a pathological condition. This state of dysbiosis is then known to feedback on depressive symptoms. While studies have demonstrated that targeted restoration of the microbiome can alleviate depressive-like symptoms in mice, translating these findings to human patients has proven challenging due to the complexity of the human microbiome. As such, there is an urgent need to identify factors upstream of microbial dysbiosis. Here we investigate the role of mucin 13 as an upstream mediator of microbiome composition changes. Using a model of chronic stress, we show that the mucosal protein, mucin 13, is selectively reduced after psychological stress exposure. We further demonstrate that the reduction of Muc13 is mediated by the Hnf4 transcription factor family. Finally, we determine that deleting Muc13 is sufficient to drive microbiome shifts and despair behaviors. These findings shed light on the mechanisms behind stress-induced microbial changes and reveal a regulator of mucin 13 expression. SummaryIn this paper, authors identified a pathway by which stress induces microbiome shifts. They found that psychological stress selectively alters a key mucosal protein, mucin 13, which in turn modifies the microbial niche to induce changes in bacterial composition.

microbiology↗

bioRxiv2022

T cell Aryl Hydrocarbon Receptor Activity Tunes the Gut Microenvironment to Sustain Autoimmunity.

Multiple sclerosis (MS) is a T cell driven autoimmune disease that attacks the myelin of the central nervous system and currently has no cure. MS etiology is linked to both the gut flora and external environmental factors but this connection is not well understood. One immune system regulator responsive to non-pathogenic external stimuli is the aryl hydrocarbon receptor (AHR). The AHR, which binds diverse molecules present in the environment in barrier tissues, is a therapeutic target for MS. However, AHRs precise function in T lymphocytes, the orchestrators of MS, has not been described. Here we show that in a mouse model of MS, T cell specific Ahr knockout leads to recovery driven by a decrease in T cell fitness. At the mechanistic level, we demonstrate that the absence of AHR changes the gut microenvironment composition to generate metabolites that impact T cell viability, such as bile salts and short chain fatty acids. Our study demonstrates a newly emerging role for AHR in mediating the interdependence between T lymphocytes and the microbiota, while simultaneously identifying new potential molecular targets for the treatment of MS and other autoimmune diseases.

immunology↗