University of Florida Genetics Institute, Gainesville, FL, USA.
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA.
Sci Rep. 2022 Feb 28;12(1):3268. doi: 10.1038/s41598-022-07238-9.
Parkinson's disease (PD) is a disabling neurodegenerative disorder in which multiple cell types, including dopaminergic and cholinergic neurons, are affected. The mechanisms of neurodegeneration in PD are not fully understood, limiting the development of therapies directed at disease-relevant molecular targets. C. elegans is a genetically tractable model system that can be used to disentangle disease mechanisms in complex diseases such as PD. Such mechanisms can be studied combining high-throughput molecular profiling technologies such as transcriptomics and metabolomics. However, the integrative analysis of multi-omics data in order to unravel disease mechanisms is a challenging task without advanced bioinformatics training. Galaxy, a widely-used resource for enabling bioinformatics analysis by the broad scientific community, has poor representation of multi-omics integration pipelines. We present the integrative analysis of gene expression and metabolite levels of a C. elegans PD model using GAIT-GM, a new Galaxy tool for multi-omics data analysis. Using GAIT-GM, we discovered an association between branched-chain amino acid metabolism and cholinergic neurons in the C. elegans PD model. An independent follow-up experiment uncovered cholinergic neurodegeneration in the C. elegans model that is consistent with cholinergic cell loss observed in PD. GAIT-GM is an easy to use Galaxy-based tool for generating novel testable hypotheses of disease mechanisms involving gene-metabolite relationships.
帕金森病（PD）是一种使人丧失能力的神经退行性疾病，其中包括多巴胺能和胆碱能神经元在内的多种细胞类型受到影响。PD 中的神经退行性机制尚未完全阐明，这限制了针对与疾病相关的分子靶标的治疗方法的发展。秀丽隐杆线虫是一种遗传上易于处理的模型系统，可用于梳理 PD 等复杂疾病中的疾病机制。可以通过转录组学和代谢组学等高通量分子分析技术来研究这些机制。然而，为了揭示疾病机制而对多组学数据进行综合分析是一项具有挑战性的任务，如果没有先进的生物信息学培训，则很难完成。Galaxy 是一个广泛用于使广大科学界能够进行生物信息学分析的资源，但它对多组学集成管道的代表性很差。我们使用新的 Galaxy 工具 GAIT-GM 对秀丽隐杆线虫 PD 模型的基因表达和代谢物水平进行了综合分析。使用 GAIT-GM，我们发现了秀丽隐杆线虫 PD 模型中支链氨基酸代谢与胆碱能神经元之间的关联。一项独立的后续实验揭示了秀丽隐杆线虫模型中的胆碱能神经退行性变，这与 PD 中观察到的胆碱能细胞丢失一致。GAIT-GM 是一种易于使用的基于 Galaxy 的工具，可用于生成涉及基因-代谢物关系的疾病机制的新的可测试假设。
