Effects of gut microbiome on the brain of alpha-synuclein overexpressing mice

Parkinson's disease (PD) pathophysiology involves gene-environment interactions that influence motor and non-motor symptoms as a result of cellular alterations including mitochondrial dysfunction. Mitochondria-associated gene mutations are causal for PD, mitochondria are altered in the PD brain, and mitochondrial-damaging toxins cause PD-like motor and gastrointestinal symptoms in animals. The gut microbiome is altered in PD patients representing an environmental risk, however the relationship between mitochondrial function and the microbiome in PD has not been established. Herein, we report that striatal mitochondria are functionally overactive in alpha-synuclein-overexpressing (ASO) mice, a model of PD, and that microbiome depletion rescues hyperactive respiration and restores mitochondria-associated gene expression patterns. ASO mice liberate increased reactive oxygen species in the striatum whereas germ-free counterparts express elevated levels of reactive-oxygen-scavenging proteins that may buffer from oxidative damage. Indeed, antioxidant treatment improves motor performance in ASO mice and, remarkably, blocking oxidant scavenging in germ-free mice induces alpha-synuclein-dependent motor deficits. Thus, the gut microbiome increases mitochondrial respiration and oxidative stress in the brain, leading to motor symptoms in a mouse model of PD.