Elizabeth Jane Videlock

Emerging evidence suggests that Parkinson’s disease (PD) may have its origin in the enteric nervous system (ENS), from where α-synuclein (αS) pathology spreads to the brain^1,2,3,4. Decades before the onset of motor symptoms, patients with PD suffer from constipation and present with circulating T cells responsive to αS, suggesting that peripheral immune responses initiated in the ENS may be involved in the early stages of PD^1,5,6,7. However, cellular mechanisms that trigger αS pathology in the ENS and its spread along the gut–brain axis remain elusive. Here we demonstrate that muscularis macrophages (ME-Macs), housekeepers of ENS integrity and intestinal homeostasis, modulate αS pathology and neurodegeneration in models of PD^8,9. ME-Macs contain misfolded αS, adopt a signature reflecting endolysosomal dysfunction and modulate the expansion of T cells that travel from the ENS to the brain through the dura mater as αS pathology progresses. Directed ME-Mac depletion leads to reduced αS pathology in the ENS and central nervous system, prevents T cell expansion and mitigates neurodegeneration and motor dysfunction, suggesting a role for ME-Macs as early cellular initiators of αS pathology along the gut–brain axis. Understanding these mechanisms could pave the way for early-stage biomarkers in PD.

Automated detection of gut Lewy Pathology using Leica Bond RX processor based on Protocol F using Bond Polymer Refine Detection kit (Leica Biosystems,Cat#: DS9800). Adapted from "Method 5" as described in Beach TG et al., J Parkinsons Dis. 2016. Acknowledgments We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona, for the provision of human colon tissue and data. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsons Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimers Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimers Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinsons Disease Consortium) and the Michael J. Fox Foundation for Parkinsons Research. We wish to acknowledge Yunfeng Li and the Translational Pathology Core Laboratory (TPCL) at UCLA for assistance with tissue processing, IHC staining, and scanning.

Automated detection of gut Lewy Pathology using Leica Bond RX processor based on Protocol F using Bond Polymer Refine Detection kit (Leica Biosystems,Cat#: DS9800). Adapted from "Method 5" as described in Beach TG et al., J Parkinsons Dis. 2016. Acknowledgments We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona, for the provision of human colon tissue and data. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsons Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimers Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimers Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinsons Disease Consortium) and the Michael J. Fox Foundation for Parkinsons Research. We wish to acknowledge Yunfeng Li and the Translational Pathology Core Laboratory (TPCL) at UCLA for assistance with tissue processing, IHC staining, and scanning.

Background: Evidence supports a role for the gut-brain axis in Parkinson’s disease (PD). Mice overexpressing human wild type α– synuclein (Thy1-haSyn) exhibit slow colonic transit prior to motor deficits, mirroring prodromal constipation in PD. Identifying molecular changes in the gut could provide both biomarkers for early diagnosis and gut-targeted therapies to prevent progression. Objective: To identify early molecular changes in the gut-brain axis in Thy1-haSyn mice through gene expression profiling. Methods: Gene expression profiling was performed on gut (colon) and brain (striatal) tissue from Thy1-haSyn and wild-type (WT) mice aged 1 and 3 months using 3^′ RNA sequencing. Analysis included differential expression, gene set enrichment and weighted gene co-expression network analysis (WGCNA). Results: At one month, differential expression (Thy1-haSyn vs. WT) of mitochondrial genes and pathways related to PD was discordant between gut and brain, with negative enrichment in brain (enriched in WT) but positive enrichment in gut. Linear regression of WGCNA modules showed partial independence of gut and brain gene expression changes. Thy1-haSyn-associated WGCNA modules in the gut were enriched for PD risk genes and PD-relevant pathways including inflammation, autophagy, and oxidative stress. Changes in gene expression were modest at 3 months. Conclusions: Overexpression of haSyn acutely disrupts gene expression in the colon. While changes in colon gene expression are highly related to known PD-relevant mechanisms, they are distinct from brain changes, and in some cases, opposite in direction. These findings are in line with the emerging view of PD as a multi-system disease.

Background: Evidence supports a role for the gut-brain axis in Parkinson Disease (PD). Mice overexpressing human wild type α–synuclein (Thy1-haSyn) exhibit slow colonic transit prior to motor deficits, mirroring prodromal constipation in PD. Identifying molecular changes in the gut could provide both biomarkers for early diagnosis and gut-targeted therapies to prevent progression. Objective: To identify early molecular changes in the gut-brain axis in Thy1-haSyn mice through gene expression profiling. Methods: Gene expression profiling was performed on gut (colon) and brain (striatal) tissue from Thy1-haSyn and wild-type (WT) mice aged 1 and 3 months using 3′ RNA sequencing. Analysis included differential expression, gene set enrichment and weighted gene co-expression network analysis (WGCNA). Results: At one month, differential expression (Thy1-haSyn vs WT) of mitochondrial genes and pathways related to PD was discordant between gut and brain, with negative enrichment in brain (enriched in WT) but positive enrichment in gut. Linear regression of WGCNA modules showed partial independence of gut and brain gene expression changes. Thy1-haSyn-associated WGCNA modules in the gut were enriched for PD risk genes and PD-relevant pathways including inflammation, autophagy, and oxidative stress. Changes in gene expression were modest at 3 months. Conclusions: Overexpression of haSyn acutely disrupts gene expression in the colon. While changes in colon gene expression are highly related to known PD-relevant mechanisms, they are distinct from brain changes, and in some cases, opposite in direction. These findings are in line with the emerging view of PD as a multi-system disease.

Background: There is strong support from studies in humans and in animal models that Parkinson's disease (PD) may begin in the gut. This brings about a unique opportunity for researchers in the field of neurogastroenterology to contribute to advancing the field and making contributions that could lead to the ability to diagnose and treat PD in the premotor stages. Lack of familiarity with some of the aspects of the experimental approaches used in these studies may present a barrier for neurogastroenterology researchers to enter the field. Much remains to be understood about intestinal‐specific components of gut‐first PD pathogenesis and the field would benefit from contributions of enteric and central nervous system neuroscientists.Purpose: To address these issues, we have conducted a systematic review of the two most frequently used experimental models of gut‐first PD: transneuronal propagation of α‐synuclein preformed fibrils and oral exposure to environmental toxins. We have reviewed the details of these studies and present methodological considerations for the use of these models. Our aim is that this review will serve as a framework and useful reference for neuroscientists, gastroenterologists, and neurologists interested in applying their expertise to advancing our understanding of gut‐first PD.

Background: Although early adverse life events (EALs) are prevalent among patients with irritable bowel syndrome (IBS), the impact of fear or dissociation experienced during the trauma has not been evaluated. We investigated the prevalence of fear at the time of trauma and its association with IBS status among individuals with early‐life trauma before the age of 18.Methods: Among participants with ≥1 EAL, association of fear and dissociation with IBS status was determined with logistic regression, and improvement in prediction of IBS over ETI score alone was determined with the likelihood ratio test. Controlling for age, sex, and IBS status, we then examined the association of each EAL with reported fear.Key Results: Compared to healthy controls (HCs), IBS subjects reported a higher prevalence of fear (60.4% vs 36.2%, P < .0005) and dissociation (23.5% vs 13.0%, P < .0005) at the time of EAL. Fear, but not dissociation, improved prediction of IBS over the total number of EALs (odds ratio = 2.00, P < .0001).Conclusions and Inferences: This study highlights the importance of EAL‐related factors such as fear in addition to the presence or absence of EALs in IBS pathophysiology.

The inflammatory bowel diseases (IBD) are a complex set of chronic gastrointestinal inflammatory conditions arising from the interplay of genetic and environmental factors. This study focuses on noncoding RNA transcripts as potential mediators of IBD pathophysiology. One particular gene, interferon γ-antisense 1 ( IFNG-AS1), has been consistently observed to be elevated in the intestinal mucosa of patients with actively inflamed IBD versus healthy controls. This study builds on these observations, demonstrating that the second splice variant is specifically altered, and this alteration even stratifies within inflamed patients. With the use of a CRISPR-based overexpression system, IFNG-AS1 was selectively overexpressed directly from its genomic loci in T cells. An unbiased mRNA array on these cells identified a large increase in many inflammatory cytokines and a decrease in anti-inflammatory cytokines after IFNG-AS1 overexpression. Media from T cells overexpressing IFNG-AS1 elicited an inflammatory signaling cascade in primary human peripheral blood mononuclear cells, suggesting the potential functional importance of IFNG-AS1 in IBD pathophysiology. The significance of these results is amplified by studies suggesting that a single-nucleotide polymorphism in IFNG-AS1, rs7134599, was associated with both subtypes of patients with IBD independently of race. NEW & NOTEWORTHY Long noncoding RNAs are an emerging field of inflammatory bowel disease (IBD) research. This study mechanistically analyzes the role of a commonly upregulated gene in IBD and shows IFNG-AS1 as a mediator of an inflammatory signaling cascade.