Project Grant R21NS137244

MODIFYING THE MICROBIOME TO ENHANCE L-DOPA THERAPY IN PARKINSON'S DISEASE - PROJECT SUMMARY/ABSTRACT PARKINSON'S DISEASE (PD) IS A PROGRESSIVE NEURODEGENERATIVE DISEASE RESULTING FROM THE LOSS OF DOPAMINERGIC NEURONS IN THE SUBSTANTIA NIGRA. IT IS THE SECOND-LEADING NEURODEGENERATIVE DISEASE ASSOCIATED WITH AGING. FOR OVER FIFTY YEARS, TREATMENT WITH LEVODOPA (L-DOPA), WHICH CROSSES THE BLOOD-BRAIN BARRIER AND IS CONVERTED TO DOPAMINE (DA), HAS BEEN USED TO MITIGATE THE DEBILITATING MOTOR SYMPTOMS ASSOCIATED WITH PD. HOWEVER, THERE ARE SEVERAL CAVEATS ASSOCIATED WITH L-DOPA THERAPY INCLUDING ERRATIC, "ON-OFF" CYCLICAL RELIEF FROM MOTOR SYMPTOMS, LARGE INDIVIDUAL VARIABILITY IN EFFECTIVE DOSE, AND A LOSS OF EFFICACY OVER TIME. THIS LOSS OF EFFICACY NECESSITATES ESCALATION OF L-DOPA DOSAGE, WITH AN INCREASED RISK OF L-DOPA INDUCED DYSKINESIA. ONE CONFOUNDING FACTOR IN L- DOPA TREATMENT IS ITS METABOLISM TO DA BY GUT MICROBIOTA. DA PRODUCED SYSTEMICALLY IS UNABLE TO CROSS THE BLOOD- BRAIN BARRIER AND IS ASSOCIATED WITH ADVERSE PHYSIOLOGICAL EFFECTS. ALTHOUGH AROMATIC AMINO ACID DECARBOXYLASE INHIBITORS (E.G., CARBIDOPA) ARE TYPICALLY CO-ADMINISTERED WITH L-DOPA, THEY ARE INEFFECTIVE AGAINST MICROBIAL METABOLISM. ENTEROCOCCUS FAECALIS, A UBIQUITOUS MEMBER OF THE GUT MICROBIOME THAT IS PRIMARILY RESPONSIBLE FOR THE BACTERIAL METABOLISM OF L-DOPA, EXPRESSES A TYROSINE DECARBOXYLASE (TYRDC) THAT AVIDLY CONVERTS L-DOPA TO DA AND IS ONLY WEAKLY INHIBITED BY CARBIDOPA. IN THE PROPOSED STUDIES, WE WILL TEST THE HYPOTHESIS THAT DELETION OF THE TYRDC GENE FROM A PREVIOUSLY ENGINEERED, BACTERIOCIN-EXPRESSING STRAIN OF E. FAECALIS WILL ABROGATE L- DOPA METABOLISM, LEADING TO INCREASED L-DOPA AND DECREASED DA IN THE SERUM, AND ELEVATED DA LEVELS IN THE BRAIN FOLLOWING ORAL L-DOPA ADMINISTRATION. IN AIM 1, WE WILL INVESTIGATE COLONIZATION OF THE MOUSE GASTROINTESTINAL TRACT WITH THE NEWLY CONSTRUCTED DTYRDC MUTANT AND DETERMINE THE IMPACT OF COLONIZATION ON L-DOPA AND DA CONCENTRATIONS IN THE BLOOD AND BRAIN FOLLOWING ORAL ADMINISTRATION OF L-DOPA. IN AIM 2, WE WILL ADDRESS THE IMPACT OF COLONIZATION WITH THE DTYRDC MUTANT ON THE EFFICACY OF ORAL L-DOPA THERAPY IN ALLEVIATING MOTOR DEFICITS AND THE DEVELOPMENT OF L-DOPA INDUCED DYSKINESIA IN A MOUSE MODEL OF PD. THE SCIENTIFIC IMPACT OF THESE STUDIES WILL BE TO FURTHER ELUCIDATE THE EFFECTS OF GUT MICROBIAL METABOLISM ON THE EFFICACY OF ORAL L-DOPA THERAPY. THERE IS A CLEAR UNMET NEED FOR NOVEL APPROACHES THAT ENHANCE OR EXTEND THE USEFULNESS OF L-DOPA IN PD TREATMENT, AND THE DEVELOPMENT OF A PROBIOTIC THAT EFFECTIVELY PREVENTS DECARBOXYLATION OF L-DOPA IN THE GASTROINTESTINAL TRACT MAY HAVE SIGNIFICANT POTENTIAL AS AN ADJUNCT TO L-DOPA IN THE MANAGEMENT OF PD.