Joanna Korecka, PhD

The gut microbiota can influence the brain and may affect neurologic diseases by modulating immune responses in the central nervous system or by secreting neuroactive metabolites. Immune mechanisms may be critical in initiating neuronal degeneration in Parkinson’s disease (PD) and interestingly, the gut microbiota can modulate microglia and animal models of neurologic diseases in a sex-specific manner. The transfer of gut microbiota to the wild-type alpha-synuclein (a-syn) overexpressing animal model of PD induced severe neurodegenerative phenotypes, however, whether there are differences in males vs. females is unknown. Furthermore, whether the gut microbiota can contribute to variable penetrance in familial PD has not been studied. We collected gut microbiota from kindred with PD and dementia that harbors a dominantly inherited PD-driving mutation (“E46K”) in the a-syn gene, presenting neurodegenerative phenotypes closely resembling idiopathic Parkinsonism. Interestingly, some mutation carriers escape the brain disease, whereas all carriers show evidence for peripheral autonomic neural disease.
To determine if the E46K kindred microbiome contributes to neurodegeneration, we colonized the 3KL PD mouse model (expressing lower a-syn levels then the original 3K line) with microbiota from male and female family members who are either (i) clinically affected E46K carriers, (ii) non-affected E46K carriers, or (iii) non-carriers healthy controls. The original 3K transgenic mice overexpress the same E46K a-syn mutation as the kindred in an “amplified” form (by caring additional analogous E46K mutations), leading to a-syn pathology and L-DOPA-dependent motor behavior dysfunction with an observed sex-dependent rate of vulnerability. We found that male 3KL mice inoculated with both late and early onset male PD patient microbiome develop motor impairments on the pole test and clasping test, when compared to male mice inoculated with non-carrier microbiota. Interestingly, female mice do not show this behavior deficit, even 4 months after weekly female PD patient microbiome transfer.

How this work applies to sex difference and gender biology:
PD is 1.5 times more common in males than in females. Our data suggests that the gut microbiota may contribute to motor deficits with a sex-specific component, however, whether these differences are mediated by change in the gut microbiota or by changes in male vs. female PD mice is still unknown. Future studies will focus on neuronal health and neuroinflammation assessment and dissection of molecular signatures underlying these phenotypes, including RNAseq analysis of the brain isolated microglia and astrocytes and bacterial sequencing of the PD patient microbiome. We will focus our analysis on understanding the underlying microbiome-induced immuno-neurodegenerative differences impacting the ‘potency’ of the altered molecular signaling induced by the kindred microbiome transfer.