The gut microbiome promotes mitochondrial respiration in the brain of a Parkinson’s disease mouse model
The pathophysiology of Parkinson's disease (PD) involves gene-environment interactions that impair various cellular processes including mitochondrial dysfunction. Mitochondria-associated mutations increase PD risk, respiration is altered in the PD brain, and mitochondria-damaging toxicants cause PD-like motor and gastrointestinal symptoms in animal models. The gut microbiome is altered in PD, representing an environmental risk, however a relationship between mitochondrial function and the microbiome in PD has not been previously established. Herein, we discover that dysregulation of mitochondria-associated genes and hyperactive striatal mitochondria are induced by the microbiome in α-synuclein-overexpressing (Thy1-ASO) mice. Thy1-ASO mice elaborate increased reactive oxygen species in the striatum whereas germ-free counterparts express increased oxygen scavenging proteins. Indeed, treatment with an antioxidant drug improves motor performance in Thy1-ASO mice and blocking oxidant scavenging in germ-free mice enhances motor deficits in an α-synuclein dependent manner. Thus, the gut microbiome promotes motor symptoms in a mouse model of PD via increased mitochondrial respiration and oxidative stress in the brain.
Authors
- Joanne Trinh (ORCID: https://orcid.org/0000-0001-9863-2070)
- Tsui‐Fen Chou (ORCID: https://orcid.org/0000-0003-2410-2186)
- Anastasiya Oguienko (ORCID: https://orcid.org/0000-0002-8473-6378)
- Jack Devine
- Lívia H. Morais (ORCID: https://orcid.org/0000-0002-5738-2658)
- Jeff Jones (ORCID: https://orcid.org/0000-0002-7142-2222)
- Baiyi Quan (ORCID: https://orcid.org/0000-0001-6313-4274)
- Jonathan D. Hoang (ORCID: https://orcid.org/0000-0002-3762-9596)
- Viviana Gradinaru (ORCID: https://orcid.org/0000-0001-5868-348X)
- Justin S. Bois (ORCID: https://orcid.org/0000-0001-7137-8746)
- Sarkis K. Mazmanian (ORCID: https://orcid.org/0000-0003-2713-1513)
- Martin Picard (ORCID: https://orcid.org/0000-0003-2835-0478)
- Jenny Ji (ORCID: https://orcid.org/0000-0002-7901-5605)
- Matthew Freeman (ORCID: https://orcid.org/0000-0003-0410-5451)
- Linsey Stiles (ORCID: https://orcid.org/0000-0002-1514-458X)
Institutions
- California Institute of Technology (US)
- University of California, Los Angeles (US)
- Columbia University Irving Medical Center (US)
- Universidade Federal de Santa Catarina (BR)
- Research Network (United States) (US)
- University of Lübeck (DE)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2025-10-20
- DOI
- https://doi.org/10.1038/s41531-025-01142-5
- Citations
- 2
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.78
Funders
- U.S. Department of Defense
- Michael J. Fox Foundation for Parkinson's Research