Distinct Patterns of Gene Expression Changes in the Colon and Striatum of Young Mice Overexpressing Alpha-Synuclein Support Parkinson's Disease as a Multi-System Process.

Autor: Videlock EJ; Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Hatami A; The Drug Discovery Lab, Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Zhu C; The Drug Discovery Lab, Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Kawaguchi R; The Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA., Chen H; Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Khan T; Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Yehya AHS; Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Stiles L; Department of Medicine, Division of Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Joshi S; G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Hoffman JM; Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Law KM; Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Rankin CR; Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Chang L; G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Maidment NT; Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., John V; The Drug Discovery Lab, Mary S. Easton Center for Alzheimer's Disease Research, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Geschwind DH; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.; Center for Autism Research and Treatment, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.; Institute for Precision Health, David Geffen School of Medicine, University of California, Los Angeles, CA, USA., Pothoulakis C; Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Jazyk: angličtina
Zdroj: Journal of Parkinson's disease [J Parkinsons Dis] 2023; Vol. 13 (7), pp. 1127-1147.
DOI: 10.3233/JPD-223568
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje