Intestinal mitochondrial dysfunction and the gut-brain-immune axis in models of Parkinson's Disease

PROJECT SUMMARY Parkinson’s Disease (PD) may begin in the gastrointestinal (GI) tract. The overall goal of this research is to identify intestinal pathogenic mechanisms in PD that may lead to the identification of gut-biomarkers for early diagnosis as well as gut-directed therapies to halt progression of disease in the premotor phase. The proposed research addresses the hypothesis that mitochondrial dysfunction in the intestinal epithelium causes PD via the gut brain immune axis through two specific aims. The first aim will determine the role of mitochondrial dysfunction in mediating the response of the intestinal epithelium to enteric neuron pathologic α-Synuclein. This will be accomplished through measurement of inflammation and mitochondrial stress in duodenal tissue, isolated crypts and intestinal organoids from a PD model (mice over-expressing human α-Synuclein). In addition, these measures will be evaluated in wild type organoids treated with conditioned media from organotypic cultures of the enteric nervous system in the same PD model. The second aim will test the hypothesis that impaired mitophagy in the intestinal epithelium causes persistent central pathology and motor deficits in a gut-seeding PD model. This will be accomplished through duodenal injection of α-Synuclein preformed fibrils in mice with intestinal epithelial-specific Parkin knockout and wild type mice. This proposed research will provide Dr. Elizabeth Videlock, a board-certified Gastroenterologist, with training in the research skills necessary to study the gut-brain axis in PD. This technical training is a component of a comprehensive career development plan designed to facilitate her transition to independence. Her mentorship team is led by Nigel Maidment, Professor of Psychiatry and Biobehavioral Sciences, who has extensive experience studying dopamine neurotransmission in rodent models of PD and a strong track record in mentoring trainees to independence. Co-mentors will provide mentorship in assessment of the enteric nervous system (Million Mulugeta), intestinal organoids (Martin G. Martin), and leadership skills (Lin Chang). In addition, an advisory panel will provide mentorship for content related to the role of the gut in PD (Yvette Taché, Michael Camilleri) and mitochondrial morphology and metabolism in epithelial cells (Leanne Jones, Rajat Singh). The strength of the clinical and basic science programs in metabolism, neurodegenerative disease and the gut-brain axis make UCLA the perfect institution to support this interdisciplinary proposal.