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 ¿tyrDC 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 ¿tyrDC 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.