Connors-BRI Symposium

Incorporating Sex as Biologic Variable to Advance Health

May 24, 2021 | 3-5PM

Virtual Event

Joanna Korecka, PhD

Brigham and Women’s Hospital


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.


3PM – Welcome Remarks
3:05PM – Keynote Address
3:45PM – Featured Short Talks
4:20PM – Lightning Talks
4:50PM – Closing Remarks

Keynote Speaker

Janine Austin Clayton, MD

Janine Austin Clayton, M.D., Associate Director for Research on Women’s Health and Director of the Office of Research on Women’s Health (ORWH) at the National Institutes of Health (NIH), is the architect of the NIH policy requiring scientists to consider sex as a biological variable across the research spectrum. This policy is part of NIH’s initiative to enhance reproducibility through rigor and transparency. As co-chair of the NIH Working Group on Women in Biomedical Careers with NIH Director Dr. Francis Collins, Dr. Clayton also leads NIH’s efforts to advance women in science careers.

Prior to joining the ORWH, Dr. Clayton was the Deputy Clinical Director of the National Eye Institute (NEI) for seven years. A board-certified ophthalmologist, Dr. Clayton’s research interests include autoimmune ocular diseases and the role of sex and gender in health and disease. She is the author of more than 120 scientific publications, journal articles, and book chapters.
Dr. Clayton, a native Washingtonian, received her undergraduate degree with honors from Johns Hopkins University and her medical degree from Howard University College of Medicine. She completed a residency in ophthalmology at the Medical College of Virginia. Dr. Clayton completed fellowship training in cornea and external disease at the Wilmer Eye Institute at Johns Hopkins Hospital and in uveitis and ocular immunology at NEI.

Dr. Clayton has received numerous awards, including the Senior Achievement Award from the Board of Trustees of the American Academy of Ophthalmology in 2008 and the European Uveitis Patient Interest Association Clinical Uveitis Research Award in 2010. She was selected as a 2010 Silver Fellow by the Association for Research in Vision and Ophthalmology. In 2015, she was awarded the American Medical Women’s Association Lila A. Wallis Women’s Health Award and the Wenger Award for Excellence in Public Service. Dr. Clayton was granted the Bernadine Healy Award for Visionary Leadership in Women’s Health in 2016. She was also selected as an honoree for the Woman’s Day Red Dress Awards and the American Medical Association’s Dr. Nathan Davis Awards for Outstanding Government Service in 2017.