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,Journal of Parkinson’s Disease

当前位置： X-MOL 学术 › J. Parkinson’s Dis. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

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
Journal of Parkinson’s Disease ( IF 5.2 ) Pub Date : 2023-08-19 , DOI: 10.3233/jpd-223568
Elizabeth J Videlock ₁ , Asa Hatami ₂ , Chunni Zhu ₂ , Riki Kawaguchi ₃ , Han Chen ₁ , Tasnin Khan ₁ , Ashwaq Hamid Salem Yehya ₁ , Linsey Stiles ₄ , Swapna Joshi ₅ , Jill M Hoffman ₁ , Ka Man Law ₁ , Carl Robert Rankin ₁ , Lin Chang ₅ , Nigel T Maidment _{6,

7} , Varghese John ₂ , Daniel H Geschwind _{8,

9,

10} , Charalabos Pothoulakis ₁

Affiliation

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.
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.
The Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
Department of Medicine, Division of Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
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.
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.
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.

Abstract

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.

中文翻译：

过度表达α-突触核蛋白的幼鼠结肠和纹状体基因表达变化的独特模式支持帕金森病是一个多系统过程

摘要

背景：

有证据支持肠-脑轴在帕金森病 (PD) 中的作用。过度表达人类野生型 α-突触核蛋白 (Thy1-haSyn) 的小鼠在运动缺陷之前表现出缓慢的结肠传输，反映了 PD 的前驱便秘。识别肠道中的分子变化可以为早期诊断和预防进展的肠道靶向治疗提供生物标志物。

客观的：

通过基因表达谱鉴定 Thy1-haSyn 小鼠肠脑轴的早期分子变化。

方法：

^{使用 3 '} RNA 测序对 Thy1-haSyn 以及 1 个月和 3 个月大的野生型 (WT) 小鼠的肠道（结肠）和大脑（纹状体）组织进行基因表达谱分析。分析包括差异表达、基因集富集和加权基因共表达网络分析（WGCNA）。

结果：

一个月时，与 PD 相关的线粒体基因和通路的差异表达（Thy1-haSyn 与 WT）在肠道和大脑之间不一致，大脑中呈负富集（WT 中富集），但肠道中呈正富集。WGCNA 模块的线性回归显示肠道和大脑基因表达变化部分独立。肠道中 Thy1-haSyn 相关的 WGCNA 模块富含 PD 风险基因和 PD 相关途径，包括炎症、自噬和氧化应激。3 个月时基因表达的变化不大。