Novel Therapeutic Targeting of Neurotoxic Gut Microbiota Derived Metabolites in Parkinson'sDisease
Abstract
Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder affecting an estimated seven to 10 million people worldwide. While its exact etiology remains largely unknown, PD is likely to be multifactorial with contributions from both genetic and environmental factors. Recent evidence suggests that the gut-brain axis plays a large role in the development of PD, and gastrointestinal dysfunction and microbiome dysbiosis have been linked to the onset and progression of PD pathology. Using advanced microbial sequencing studies in the gut microbiomes of PD patients, we recently uncovered that the microbial pathways for synthesis of a neurotoxic chemical, trimethylamine (TMA) was highly elevated in PD patients. Microbiota-derived TMA is metabolized in the liver to trimethylamine N-oxide (TMAO), which enters systemic circulation and crosses the blood brain barrier and has been shown to accelerate the rate of -synuclein (Syn) fibril formation. Additionally, microbial TMA can also be converted into toxic metabolites formaldehyde (HCHO) and ammonia (NH3). Our preliminary studies also found significantly elevated plasma TMAO and HCHO production in PD patients. Our subsequent mechanistic studies further revealed that TMAO treatment promotes Syn aggregation and stabilize its conformational changes and triggers inflammasome activation. Our proposed studies will test the following 3 objectives. In Objective 1, we will identify the TMA-generating bacterial species and strains that are elevated in human PD and establish the link between neurotoxic TMAO and HCHO metabolites, aggregated Syn load and gut and peripheral inflammatory markers. In Objective 2, we will evaluate the therapeutic potential of pharmacological inhibitors of bacterial TMA production for disease modification in PD using well-established transgenic and humanized germ-free mouse models of PD.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1218458
Entities
People
- Anumantha G Kanthasamy
Organizations
- University of Georgia