alpha-synuclein and Inflammatory-Bowel-Diseases

Parkinson's disease (PD) has long been considered a brain disease, but studies now point to the gastrointestinal (GI) tract as a potential starting point for PD. In particular, the human vermiform appendix has been implicated in PD. The appendix is a tissue rich in immune cells, serving as part of the gut-associated lymphoid tissue and as a storehouse for the gut microbiome. The functions of the appendix converge with recent evidence demonstrating that gut inflammation and shifts in the microbiome are linked to PD. Some epidemiological studies have linked removal of the appendix to lowered PD risk, though there is controversy among these associations. What is apparent is that there is an abundance of aggregated forms of α-synuclein in the appendix relevant to PD pathology. α-Synuclein pathology is thought to propagate from gut to brain via the vagus nerve, which innervates GI tract locations, including the appendix. Remarkably, α-synuclein aggregates in the appendix occur not only in PD patients, but are also present in healthy individuals. This has led to the proposal that in the appendix α-synuclein aggregates are not unique to PD. Moreover, the molecular events leading to PD and the mechanisms by which α-synuclein aggregates transfers from gut to brain may be identifiable in the human appendix. The influence of the appendix on GI inflammation, autoimmunity, microbiome storage, and the lymphatic system may be yet unexplored mechanisms by which the appendix contributes to PD. Overall, the appendix represents a promising tissue site to advance our understanding of PD pathobiology.

Topics: alpha-Synuclein; Animals; Appendix; Gastrointestinal Microbiome; Humans; Immune System; Inflammatory Bowel Diseases; Lymphatic System; Parkinson Disease

Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by intracellular accumulations of α-synuclein and nerve cell loss in striatonigral and olivopontocerebellar structures. Epidemiological and clinical studies have reported potential involvement of autoimmune mechanisms in MSA pathogenesis. However, genetic etiology of this interaction remains unknown. We aimed to investigate genetic overlap between MSA and 7 autoimmune diseases and to identify shared genetic loci.. Genome-wide association study summary statistics of MSA and 7 autoimmune diseases were combined in cross-trait conjunctional false discovery rate analysis to explore overlapping genetic background. Expression of selected candidate genes was compared in transgenic MSA mice and wild-type mice. Genetic variability of candidate genes was further investigated using independent whole-exome genotyping data from large cohorts of MSA and autoimmune disease patients and healthy controls.. We observed substantial polygenic overlap between MSA and inflammatory bowel disease and identified 3 shared genetic loci with leading variants upstream of the DENND1B and RSP04 genes, and in intron of the C7 gene. Further, the C7 gene showed significantly dysregulated expression in the degenerating midbrain of transgenic MSA mice compared with wild-type mice and had elevated burden of protein-coding variants in independent MSA and inflammatory bowel disease cohorts.. Our study provides evidence of shared genetic etiology between MSA and inflammatory bowel disease with an important role of the C7 gene in both phenotypes, with the implication of immune and gut dysfunction in MSA pathophysiology. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Topics: alpha-Synuclein; Animals; Genome-Wide Association Study; Humans; Inflammatory Bowel Diseases; Mice; Mice, Transgenic; Multiple System Atrophy

Topics: alpha-Synuclein; Enteric Nervous System; Humans; Inflammatory Bowel Diseases; Parkinson Disease; Up-Regulation

Gastrointestinal (GI) symptoms can precede by many years the motor symptoms of Parkinson's disease (PD) and these patients can show some degree of inflammation associated with abnormal aggregates of alpha-synuclein in the GI tract. The abnormal accumulation of alpha-synuclein and the spreading of the aggregates from the gut to the brain might be promoted by inflammation, rising the hypothesis of a possible relationship between inflammatory bowel disease and PD. Many population-based studies have explored this association, but they have found conflicting results. It is essential to clarify this hypothesis and to try to elucidate the milestones of this relationship. There is no clear concordance between the results and the interpretation of different previous findings, probably due to many confounding factors such as drugs with anti-inflammatory activity, surgery, genetic predisposition and also selection bias. If there is a real association between both diseases, gastroenterologists and neurologists should be able to detect possible triggers of the disease or on the other hand, protective factors, that may be considered in clinical practice.

Topics: alpha-Synuclein; Brain; Enteric Nervous System; Gastrointestinal Tract; Humans; Inflammatory Bowel Diseases; Parkinson Disease; Protein Aggregates

We aimed to compare immunoreactivity patterns of four different anti-α-syn antibodies in surgical specimens of the gastrointestinal tract of Parkinson disease and control cases. Surgical specimens from stomach, small and large bowel of 6 PD cases and 12 controls were studied. Primary antibodies: anti-α-syn clone KM51, anti-phosphorylated α-syn Ser129, anti-α-syn clone 15G7 and anti-nitrated α-syn505. We found different immunoreactivity patterns: (a) coarse, Lewy-body-like aggregates labelled by the 4 antibodies and detected in 4/6 PD cases and in 1/12 controls; (b) distinct punctate cytoplasmic staining of ganglion cells labelled by anti-phosphorylated-α-syn and detected in 3/6 PD cases and 3/12 controls; (c) fine diffuse, synaptic-type staining of neural structures labelled by anti-α-syn-15G7 and anti-nitrated-α-syn505 and detected in all subjects. We conclude that different specific and non-specific immunoreactivity patterns are detected in surgical specimens of gastrointestinal tract when using different anti-α-syn antibodies, as they recognize different epitopes and states of alpha-synuclein protein. Coarse aggregates in neural structures seem to be the most promising marker for the diagnosis of Lewy-body parkinsonism when evaluating abnormal α-syn in the gastrointestinal tract.

Topics: Adult; Aged; Aged, 80 and over; alpha-Synuclein; Biomarkers; Case-Control Studies; Colonic Neoplasms; Enteric Nervous System; Female; Gastrointestinal Tract; Humans; Inflammatory Bowel Diseases; Lewy Bodies; Male; Middle Aged; Myenteric Plexus; Parkinson Disease; Protein Aggregates; Young Adult