Molecular mechanisms of mitochondrial dysfunction in ATP13A2-associated neurodege

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DESCRIPTION (provided by applicant): I am a pediatric neurologist with a long-standing interest in neurodegenerative disease. I have been trained in molecular genetics, and have published over 20 peer-reviewed publications, 10 as first author. In the long-term, I am committed to do everything possible to bring new treatments to my patients with neurodegenerative disorders, whether these therapies come from my lab or that of a colleague. However, a significant gap exists between my present skill set and the work I plan to pursue as an independent investigator. In order to fully dissect mechanisms of disease, I will need to bridge this gap with furthered mentored training that will allow me to develop expertise in mitochondrial biology and yeast and mouse model systems. The studies proposed within my K08 will do just that, while also allowing me to build a meaningful foundation to launch my research career. For my K08 studies, I will partner with mentor David Pearce. David is an energetic and dynamic investigator who has studied neuronal carotid lipofuscinosis using yeast and mouse models for almost 20 years. My own project focuses on ATP13A2 (PARK9), a lysosomal P5B ATPase, and its yeast orthodox ypk9 (yeast PARK9). PARK9 loss of function leads to both Parkinsonism and neuronal carotid lipofuscinosis. My work seeks to understand the etiology of the profound mitochondrial dysfunction that occurs with PARK9 loss, which is particularly relevant given the strong link between Parkinsonism and bioenergetics failure. My preliminary data indicates that Ypk9p deficiency leads to markedly diminished respiratory chain complex activity and increased sensitivity to reactive oxygen species, as well as mitochondrial fragmentation. These findings are independent of the effects of a-syncline. In addition, we have newly recognized that PARK9 is also found within the mitochondria-associated ER membrane (MAM) in both yeast and mammalian cells. The MAM is an important subdomain that functionally integrates cross-talk between the ER and mitochondria, and has been implicated in the biology of neurodegeneration. In order to develop my research skills, I will work at the bench alongside several talented scientists at Sanford Research. This experience will afford me the opportunity to become adept with both yeast and mouse systems, and to exploit the relative strengths of each model in the most appropriate contexts. I will have the benefit of regular interactions with Dr. Pearce and a talented cadre of collaborators at Sanford Research, each of whom will lend their expertise to facilitate my ongoing training, and equally importantly, the project's success. In addition, I will travel to Johns Hopkins, where I will train in Hiromi Sesakis lab. Hiromi is an expert in mitochondrial dynamics in both yeast and murine systems, and this represents a tremendous opportunity to rapidly develop as an investigator. In addition to this hands-on training, I will take several short courses. These courses will help me to develop expertise in mitochondrial biology and yeast and mouse systems to complement my practical experience. I will also take courses in leadership development and biostatistics and computational methods to round out my education. I am fortunate to have enthusiastic support from my institution, Sanford Research, which has already provided me with 75% protected time for research, dedicated space, access to cores and needed equipment, and an institutional allowance to help establish my research program. Sanford Health represents a rapidly growing tertiary care medical system within the Upper Midwest which was transformed by a historic $400 million gift in 2007 from philanthropist T. Denny Sanford. In the last 5 years, Sanford has grown to include locations in 112 communities in seven states with international sites in Ireland, Ghana, Israel and Mexico. Sanford Health encompasses 20,000 employees, 34 hospitals, and nearly 1000 physicians in 70 specialty areas of medicine, while Sanford Research has grown to include nearly 50 independent research groups. Sanford Research is committed to developing cutting-edge translational programs that will benefit patients throughout the region and the world. Dr. Pearce is committed to my success, and I have already grown tremendously during my first faculty year with him as my mentor. I am fortunate to have the support of a number of talented colleagues and collaborators. This includes Sergio Padilla-Lopez (yeast genetics and biochemistry, mitochondrial biology), Pete Vitiello (redox biology), Jill Weimer (mouse models of neurodegeneration), Keith Miskimins (mitochondrial dynamics and function in disease), and Attila Kovacs (mouse phenotyping and primary neuronal culture). All enthusiastically support my application, and have contributed Statements of Support. My specific aims seek to 1) identify the fundamental mechanisms that lead to mitochondrial failure in PARK9-associated disease; 2) determine the function of PARK9 within the MAM; and 3) correlate mitochondrial structure and function with the emergence of disease in an ATP13A2 knockout mouse. Accomplishing these aims will allow me to develop the expertise I need to develop an innovative independent research program while laying the foundation for subsequent treatment studies. I am grateful to be considered for this award.