Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders

Abstract

Public reporting burden for this collection of InformaUion is estimated to average 1 hour per response, including the time for reviewing instructions, searching exsting data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information, Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and The initial three years of this project determined the contributions of bioenergetic defects and oxidative sress to neurodegenertion in Huntington's disease (HD) and amyotrophic lateral sclerouis (ALS), as previously reporto•. The current report period covms the second year of work on the Consortium project "Mitochondrial Free Radical Generation in Parkinson's Disease", which was appended to the original grant number. This project is to assess in vivo whether mitochondria are the source of free radical generation in animal models of Parkinson's disease (PD). In this period of the study we have continued studies examining the relationship between mitochondrial complex I inhibition and free radical-mediated oxidative damage. Using in vivo approaches we are optimizing the doses and time-courses for detection of complex I inhibition and reactive oxygen species (ROS) generation after intracerebral administration of rotenone and pyridaben. We have found increased production of the DNA oxidative damage marker 8-hydroxydeoxyguanosine (8-OHdG) shortly (1 hour) after rotenone injection into rat striatum. Lipid peroxidation and induction of the stress-response marker heme oxygenase-I follow DNA oxidation, concomitant with complex I inhibition. Due to an unforeseen change in personnel, a no-cost extension of one year was requested, and granted, to complete these studies in the forthcoming year. INTRODUCTIONThe goal of the original three-year grant proposal was to gain insight into the roles of mitochondrial energy metabolism and oxidative stress in the etiology of neuronal degeneration in degenerative diseases, specifically Huntington's disease (HD) and amyotrophic lateral sclerosis Findings may give insight into potential drug targets for PD. These questions are somewhat easier to address by in vitro approaches (covered in other projects within the Consortium), given the extreme technical difficulties of discretely measuring purely mitochondrial events in vivo. Therefore we are taking an indirect approach, by measuring the time-course and nature of oxidative events caused by toxic insults directed against discrete mitochondrial components. Results for the second year of this consortium project are presented here. NB: In the course of this second year the post-doctoral fellow conducting the bulk of these studies left the department. Since it took some time to recruit a replacement, a no-cost extension of one year was requested, and grant...