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Updated: Jun 14, 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 α-synuclein contribute to synucleinopathies, including Parkinson's disease (PD). Most cases of PD arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms in animal models. We quantitatively profiled nearly 630 metabolites in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice, compared to wild-type (WT) animals, and comparing germ-free (GF) to specific pathogen-free (SPF) animals (n = 5 WT-SPF; n = 6 ASO-SPF; n = 6 WT-GF; n = 6 ASO-GF). Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. The microbial metabolite trimethylamine N-oxide (TMAO) strongly correlates from the gut to the plasma to the brain in mice, notable since TMAO is elevated in the blood and cerebrospinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and microbiome in a mouse model of PD.
Insights
Parkinson's disease (PD) involves altered gut bacteria and metabolites. This study found that specific gut microbial metabolites, like TMAO, correlate with PD pathology in mice, offering insights into gene-environment interactions in PD.
Area of Science:
- Neuroscience
- Metabolomics
- Microbiome Research
Background:
- Pathological alpha-synuclein is central to synucleinopathies like Parkinson's disease (PD).
- PD pathogenesis often involves complex gene-environment interactions.
- Altered gut microbiome composition is observed in PD patients and influences disease in animal models.
Purpose of the Study:
- To quantitatively profile metabolites in the gut, plasma, and brain of alpha-synuclein-overexpressing (ASO) mice.
- To compare metabolic profiles between germ-free (GF) and specific pathogen-free (SPF) conditions.
- To identify metabolic changes influenced by the interplay of host genetics and the microbiome in a PD mouse model.
Main Methods:
- Quantitative metabolomic profiling of nearly 630 metabolites.
- Comparison of α-synuclein-overexpressing (ASO) mice with wild-type (WT) littermates.
- Analysis across gut, plasma, and brain tissues in both germ-free (GF) and specific pathogen-free (SPF) conditions.
Main Results:
- Numerous differentially expressed metabolites in ASO mice mirrored those dysregulated in human PD patients, including amine oxides, bile acids, and indoles.
- The microbial metabolite trimethylamine N-oxide (TMAO) showed strong correlations from gut to plasma to brain.
- TMAO levels were elevated in the blood and cerebrospinal fluid of human PD patients.
Conclusions:
- Metabolomic profiling reveals broad changes influenced by host genetics and microbiome interactions in a PD mouse model.
- Microbial metabolites, particularly TMAO, represent a potential link between the gut microbiome and brain pathology in PD.
- These findings highlight the significance of the gut-brain axis in PD pathogenesis.
