Back when James Parkinson first described the disorder now known as Parkinson’s disease, he noticed that severe constipation can be a prelude to the signature tremors. In the 208 years since then, researchers have learned that years before a die-off of dopamine-signaling neurons in the brain causes trouble with movement, damage spreads in the neurons surrounding the gut.
In 2016, researchers found that in animal models, changes to the gut microbiome are enough to trigger the long process of neurodegeneration. According to Sarkis Mazmanian, a California Institute of Technology researcher who led that study, other labs have replicated the results enough that researchers are starting to ask, “OK, so what is it about the microbiome?”
In a talk on Monday in the Division of Biological Chemistry at the American Chemical Society Spring 2025 meeting, University of California, Irvine, professor Elizabeth Bess presented on one possible molecular mechanism that might tie microbiome problems to protein aggregation and neuron death.
The immediate cause of death in dopamine-signaling neurons is a protein called α-synuclein, which clumps into prion-like aggregates. Researchers know that in the brain, the neurotransmitter dopamine accelerates α-synuclein aggregation, especially when it is oxidized into dopamine quinone. Bess and her colleagues wondered whether the same pathway could be at work in the gut—and they found that, indeed, dopamine quinone can be formed by microbial metabolism (ACS Chem. Biol 2024, DOI: 10.1021/acschembio.4c00095).
When oxygen is unavailable, some gut bacteria can use nitrate as an alternative electron acceptor for cellular respiration, generating nitrite. The nitrite oxidizes iron, which in turn can oxidize dopamine, forming dopamine quinone. Bess and her team showed that when they exposed cultured enteroendocrine cells to nitrite, they could see the same α-synuclein aggregation as in the gut—and they saw the same when they introduced nitrite into a worm model of α-synuclein aggregation.
In a follow-up study, the team showed that some dietary polyphenols—such as caffeic acid, which is found in coffee—can outcompete dopamine to be oxidized by nitrite, protecting enteroendocrine cells from synuclein aggregation. Although this must still be tested in an animal model, Bess told C&EN that the finding suggests such molecules could have a protective effect. Additional groups have identified other specific microbial metabolites that might play a role in α-synuclein aggregation and other factors in the development of Parkinson’s disease. Mazmanian, for example, holds several patents on using gut microbes to delay the disease’s onset by producing short-chain fatty acids or bacterial amyloid inhibitors. A company he cofounded, Axial Therapeutics, is developing the latter approach.