α-Synuclein and Noradrenergic Modulation of Immune Cells in Parkinson’s Disease Pathogenesis

α-synuclein (α-syn) pathology and loss of noradrenergic neurons in the locus coeruleus (LC) are among the most ubiquitous features of Parkinson’s disease (PD). While noradrenergic dysfunction is associated with non-motor symptoms of PD, preclinical research suggests that the loss of LC norepinephrine (NE), and subsequently its immune modulatory and neuroprotective actions, may exacerbate or even accelerate disease progression. In this review, we discuss the mechanisms by which α-syn pathology and loss of central NE may directly impact brain health by interrupting neurotrophic factor signaling, exacerbating neuroinflammation, and altering regulation of innate and adaptive immune cells

Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration

Neutrophil [polymorphonuclear leukocyte (PMN)] transepithelial migration (TEM) is a hallmark of inflammatory mucosal disorders. PMN TEM is associated with epithelial injury; however, mechanisms involved in this process are not well defined. The current work describes a new mechanism whereby deposition of PMN membranederived microparticles (PMNâ MPs) onto intestinal epithelial cells (IECs) during TEM leads to loss of epithelial cadherins, thus promoting epithelial injury and increased PMN recruitment. PMNâ MPs secreted by activated PMNs during TEM displayed a high level of enzymatically activematrixmetalloproteinase 9 (MMPâ 9), and were capable of mediating potent effects on IEC integrity. Isolated PMNâ MPs efficiently bound to IEC monolayers and induced cleavage of desmogleinâ 2 (DSGâ 2) but not Eâ cadherin, leading to disruption of IEC intercellular adhesions. Furthermore, PMNâ MP binding to intestinal epithelium in vitro in transwell assays and in vivo in ligated intestinal loop preparations facilitated increases in PMN TEM. These effects were MMPâ 9 dependent and were reversed in the presence of specific pharmacological inhibitors. Finally, we demonstrated that IEC Dsgâ 2 serves as a barrier for migrating PMNs, and its removal by PMNâ MPâ associated MMPâ 9 facilitates PMNtrafficking across epithelial layers. Our findings thus implicate PMNâ MPs in PMNâ mediated inflammation and epithelial damage, as observed in inflammatory disorders ofmucosal surfaces.â Butinâ Israeli, V., Houser, M.C., Feng, M., Thorp, E. B., Nusrat, A., Parkos, C. A, Sumagin, R. Deposition of microparticles by neutrophils onto inflamed epithelium: anewmechanism to disrupt epithelial intercellular adhesions and promote transepithelialmigration. FASEB J. 30, 4007â 4020 (2016). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154234/1/fsb2fasebj30120734r.pd

Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson's disease

Background Previous studies have reported that gut microbiota, permeability, short-chain fatty acids (SCFAs), and inflammation are altered in Parkinson's disease (PD), but how these factors are linked and how they contribute to disease processes and symptoms remains uncertain. This study sought to compare and identify associations among these factors in PD patients and controls to elucidate their interrelations and links to clinical manifestations of PD. Methods Stool and plasma samples and clinical data were collected from 55 PD patients and 56 controls. Levels of stool SCFAs and stool and plasma inflammatory and permeability markers were compared between patients and controls and related to one another and to the gut microbiota. Results Calprotectin was increased and SCFAs decreased in stool in PD in a sex-dependent manner. Inflammatory markers in plasma and stool were neither intercorrelated nor strongly associated with SCFA levels. Age at PD onset was positively correlated with SCFAs and negatively correlated with CXCL8 and IL-1 beta in stool. Fecal zonulin correlated positively with fecal NGAL and negatively with PD motor and non-motor symptoms. Microbiota diversity and composition were linked to levels of SCFAs, inflammatory factors, and zonulin in stool. Certain relationships differed between patients and controls and by sex. Conclusions Intestinal inflammatory responses and reductions in fecal SCFAs occur in PD, are related to the microbiota and to disease onset, and are not reflected in plasma inflammatory profiles. Some of these relationships are distinct in PD and are sex-dependent. This study revealed potential alterations in microbiota-host interactions and links between earlier PD onset and intestinal inflammatory responses and reduced SCFA levels, highlighting candidate molecules and pathways which may contribute to PD pathogenesis and clinical presentation and which warrant further investigation.Peer reviewe

Bacterial Butyrate in Parkinson's Disease Is Linked to Epigenetic Changes and Depressive Symptoms

Background The gut microbiome and its metabolites can impact brain health and are altered in Parkinson's disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Objectives Here, we investigate whether the changes in the gut microbiome and associated metabolites are related to PD symptoms and epigenetic markers in leucocytes and neurons. Methods Stool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified genome-wide DNA methylation by targeted bisulfite sequencing. Results We show that lower fecal butyrate and reduced counts of genera Roseburia, Romboutsia, and Prevotella are related to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA regions in PD overlap with those altered in gastrointestinal (GI), autoimmune, and psychiatric diseases. Conclusions Decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes and neurons from PD patients and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain GI and psychiatric disorders, which could be relevant for their epidemiological relation. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyPeer reviewe

Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration

Neutrophil [polymorphonuclear leukocyte (PMN)] transepithelial migration (TEM) is a hallmark of inflammatory mucosal disorders. PMN TEM is associated with epithelial injury; however, mechanisms involved in this process are not well defined. The current work describes a new mechanism whereby deposition of PMN membranederived microparticles (PMNâ MPs) onto intestinal epithelial cells (IECs) during TEM leads to loss of epithelial cadherins, thus promoting epithelial injury and increased PMN recruitment. PMNâ MPs secreted by activated PMNs during TEM displayed a high level of enzymatically activematrixmetalloproteinase 9 (MMPâ 9), and were capable of mediating potent effects on IEC integrity. Isolated PMNâ MPs efficiently bound to IEC monolayers and induced cleavage of desmogleinâ 2 (DSGâ 2) but not Eâ cadherin, leading to disruption of IEC intercellular adhesions. Furthermore, PMNâ MP binding to intestinal epithelium in vitro in transwell assays and in vivo in ligated intestinal loop preparations facilitated increases in PMN TEM. These effects were MMPâ 9 dependent and were reversed in the presence of specific pharmacological inhibitors. Finally, we demonstrated that IEC Dsgâ 2 serves as a barrier for migrating PMNs, and its removal by PMNâ MPâ associated MMPâ 9 facilitates PMNtrafficking across epithelial layers. Our findings thus implicate PMNâ MPs in PMNâ mediated inflammation and epithelial damage, as observed in inflammatory disorders ofmucosal surfaces.â Butinâ Israeli, V., Houser, M.C., Feng, M., Thorp, E. B., Nusrat, A., Parkos, C. A, Sumagin, R. Deposition of microparticles by neutrophils onto inflamed epithelium: anewmechanism to disrupt epithelial intercellular adhesions and promote transepithelialmigration. FASEB J. 30, 4007â 4020 (2016). www.fasebj.or

Unsupervised Hierarchical Clustering of Head and Neck Cancer Patients by Pre-Treatment Plasma Metabolomics Creates Prognostic Metabolic Subtypes

There is growing evidence that the metabolism is deeply intertwined with head and neck squamous cell carcinoma (HNSCC) progression and survival but little is known about circulating metabolite patterns and their clinical potential. We performed unsupervised hierarchical clustering of 209 HNSCC patients via pre-treatment plasma metabolomics to identify metabolic subtypes. We annotated the subtypes via pathway enrichment analysis and investigated their association with overall and progression-free survival. We stratified the survival analyses by smoking history. High-resolution metabolomics extracted 186 laboratory-confirmed metabolites. The optimal model created two patient clusters, of subtypes A and B, corresponding to 41% and 59% of the study population, respectively. Fatty acid biosynthesis, acetyl-CoA transport, arginine and proline, as well as the galactose metabolism pathways differentiated the subtypes. Relative to subtype B, subtype A patients experienced significantly worse overall and progression-free survival but only among ever-smokers. The estimated three-year overall survival was 61% for subtype A and 86% for subtype B; log-rank p = 0.001. The association with survival was independent of HPV status and other HNSCC risk factors (adjusted hazard ratio = 3.58, 95% CI: 1.46, 8.78). Our findings suggest that a non-invasive metabolomic biomarker would add crucial information to clinical risk stratification and raise translational research questions about testing such a biomarker in clinical trials

The impact of heat exposures on biomarkers of AKI and plasma metabolome among agricultural and non-agricultural workers

Background: Agricultural workers are consistently exposed to elevated heat exposures and vulnerable to acute kidney injury. The underlying pathophysiology and detailed molecular mechanisms of AKI among agricultural workers, and the disproportionate burden of HRI and heat stress exposure are not well understood, especially at the level of cellular metabolism. Objective: The aim of this study was to examine the impact of heat exposures on renal biomarkers and on the human metabolome via untargeted high-resolution metabolomics among agricultural and non-agricultural workers. Methods: Blood and urine samples were collected pre- and post-work shift from 63 agricultural workers and 27 non– agricultural workers. We evaluated pre- and post-work shift renal biomarkers and completed untargeted metabolomics using high-resolution mass spectrometry with liquid chromatography. Metabolome-wide association studies (MWAS) models identified the metabolic features differentially expressed between agricultural workers and non-agricultural workers. Results: Median values of pre-shift creatinine and osteopontin (p < 0.05) were higher for agricultural workers than non-agricultural workers. Metabolic pathway enrichment analyses revealed 27 diverse pathways differed between agricultural workers and non-agricultural workers (p < 0.05) including TCA cycle and urea cycle, carbohydrate metabolism, histidine metabolism and evidence for altered microbiome shikimate pathway. Conclusion: This is the first investigation on the metabolic pathways that are affected among agricultural workers who are exposed to heat compared to non-heat exposed workers. This study shows extensive responses of central metabolic systems to heat exposures that impact human health

Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice

The mechanisms underlying the association between chronic psychological stress, development of metabolic syndrome (MetS), and behavioral impairment in obesity are poorly understood. The aim of the present study was to assess the effects of mild chronic psychological stress on metabolic, inflammatory, and behavioral profiles in a mouse model of diet-induced obesity. We hypothesized that (1) high-fat high-fructose diet (HFHF) and psychological stress would synergize to mediate the impact of inflammation on the central nervous system in the presence of behavioral dysfunction, and that (2) HFHF and stress interactions would impact insulin and lipid metabolism. C57BI/6 male mice underwent a combination of HFHF and two weeks of chronic psychological stress. MetS-related conditions were assessed using untargeted plasma metabolomics, and structural and immune changes in the gut and liver were evaluated. Inflammation was measured in plasma, liver, gut, and brain. Our results show a complex interplay of diet and stress on gut alterations, energetic homeostasis, lipid metabolism, and plasma insulin levels. Psychological stress and HFHF diet promoted changes in intestinal tight junctions proteins and increases in insulin resistance and plasma cholesterol, and impacted the RNA expression of inflammatory factors in the hippocampus. Stress promoted an adaptive anti-inflammatory profile in the hippocampus that was abolished by diet treatment. HFHF increased hippocampal and hepatic Lcn2 mRNA expression as well as LCN2 plasma levels. Behavioral changes were associated with HFHF and stress. Collectively, these results suggest that diet and stress as pervasive factors exacerbate MetS-related conditions through an inflammatory mechanism that ultimately can impact behavior. This rodent model may prove useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders. (C) 2016 Elsevier Inc. All rights reserved.Emory Multiplexed Immunoassay Core (EMIC)Emory University School of MedicineNational Center for Advancing Translational Sciences of the National Institutes of HealthNational Institutes of Health (NIH)/National Institute of Mental Health (NIMH)Emory Univ, Sch Med, Dept Physiol, 605L Whitehead Biomed Res Bldg,615 Michael St, Atlanta, GA 30322 USAEmory Univ, Sch Med, Div Pulm Allergy & Crit Care Med, Atlanta, GA USAUniv Fed Sao Paulo, Dept Physiol Nutr, Sao Paulo, SP, BrazilEmory Univ, Sch Med, Div Pulm Allergy & Crit Care Med, Clin Biomarkers Lab, Whitehead Biomed Res Bldg,Room 225, Atlanta, GA USAUniv Fed Sao Paulo, Dept Fisiol, Disciplina Fisiol Nutr, Edificio Ciencias Biomed,Rua Botucatu 862, BR-04023060 Sao Paulo, SP, BrazilDepartamento de Fisiologia, Disciplina de Fisiologia da Nutrição, Universidade Federal de São Paulo, Edifício de Ciências Biomédicas, Rua Botucatu 862, Vila Clementino, 04023060 São Paulo, SP, BrazilNational Center for Advancing Translational Sciences of the National Institutes of Health: UL1TR000454NIH/NIMHS: 1R43MH105048-01A1Web of Scienc