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Updated: Jun 15, 2026
Detection of Disease-associated α-synuclein by Enhanced ELISA in the Brain of Transgenic Mice Overexpressing Human A53T Mutated α-synuclein
Published on: May 30, 2015
α-Synuclein Overexpression and the Microbiome Shape the Gut and Brain Metabolome in Mice
Livia H Morais1,2, Joseph C Boktor1,2, Siamak MahmoudianDehkordi3
1Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Abstract:
Pathological forms of the protein α-synuclein contribute to a family of disorders termed synucleinopathies, which includes Parkinson's disease (PD). Most cases of PD are believed to arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms and pathology in animal models. To explore how the microbiome may impact PD-associated genetic risks, we quantitatively profiled nearly 630 metabolites from 26 biochemical classes in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice with or without microbiota. We observe tissue-specific changes driven by genotype, microbiome, and their interaction. Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. Notably, levels of the microbial metabolite trimethylamine N-oxide (TMAO) strongly correlate from the gut to the plasma to the brain, identifying a product of gene-environment interactions that may influence PD-like outcomes in mice. TMAO is elevated in the blood and cerebral spinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and the microbiome in a mouse model of PD.
Insights
Parkinson's disease (PD) risk is linked to gene-environment interactions. This study reveals how gut microbiome and genetics influence metabolite changes, like trimethylamine N-oxide (TMAO), in PD mouse models and patients.
Area of Science:
- Neuroscience
- Metabolomics
- Microbiome Research
Background:
- Pathological alpha-synuclein (α-synuclein) aggregates cause synucleinopathies, including Parkinson's disease (PD).
- PD often results from gene-environment interactions, with altered gut microbiome composition implicated in disease pathology.
- Gut bacteria can influence PD symptoms and pathology in animal models.
Purpose of the Study:
- To investigate how the gut microbiome interacts with host genetics to affect metabolic profiles in a mouse model of PD.
- To identify specific metabolites that are altered due to the interplay of genotype and microbiome in the context of PD-associated risks.
Main Methods:
- Quantitative profiling of approximately 630 metabolites across 26 biochemical classes.
- Analysis of gut, plasma, and brain samples from α-synuclein-overexpressing (ASO) mice, with and without a microbiome.
- Comparison of metabolomic data between ASO mice and human PD patients.
Main Results:
- Tissue-specific metabolic changes were observed, influenced by host genotype, microbiome, and their interaction.
- Metabolites such as amine oxides, bile acids, and indoles were dysregulated in ASO mice, mirroring changes seen in human PD.
- Trimethylamine N-oxide (TMAO), a microbial metabolite, showed strong gut-to-plasma-to-brain correlation and was elevated in PD patients.
Conclusions:
- The intersection of host genetics and the microbiome significantly influences broad metabolomic changes in a PD mouse model.
- Microbial metabolite TMAO represents a potential link between gene-environment interactions and PD-like outcomes.
- Findings highlight the role of the microbiome in modulating PD-associated metabolic alterations.
