This proposal provides a mentored career development plan and research proposal designed to facilitate the principal investigator's development into a fully independent clinician-researcher, with the goal of making significant contributions in understanding mitochondrial involvement in Parkinson's disease (PD) and other neurodegenerative diseases. Mitochondrial dysfunction is increasingly implicated in neurodegenerative diseases, particularly in PD. In addition, these are diseases of aging neurons, and mitochondrial impairment may contribute to the vulnerability of aging neurons to additional insult. However, many age-related changes in neuronal mitochondrial function and maintenance are-still not well understood. Mitochondria are dynamic organelles, undergoing frequent division (fission), fusion, and transport. These dynamic processes are critical for synapse formation and function, which has implications for pathogenesis, potential therapeutics, and late complications in PD. In addition, mitochondrial fission and fusion are centrally involved in cell death mechanisms and protection against mitochondrial DNA damage, and specific defects in mitochondrial fusion genes cause neurodegenerative diseases. In PD, the selectively vulnerable neurons all contain long and thin axons, which are more dependent on proper mitochondrial maintenance and dynamics. Yet these mitochondrial processes have been difficult to study directly, and much is not known about age-related changes or in dopaminergic neurons or chronic models of PD. Using a novel method developed to directly measure fusion and fission in individual mitochondria in live neurons and additional investigative methods, the proposed studies will 1) evaluate age-related changes in neuronal mitochondrial dynamics; 2) determine whether mitochondrial dynamics are altered in a chronic model of PD, and, importantly, whether regulating these processes can be neuroprotective; and 3) evaluate the influence of parkin on mitochondrial dynamics and its regulators, since parkin has similarities to known regulators of mitochondrial dynamics. These studies could potentially lay the groundwork for new mitochondrial therapeutic targets in PD. In addition to the proposed research, a customized career development plan is detailed, under the mentorship of an expert in neurodegenerative diseases, and utilizing the expertise of experienced senior scientists, relevant, training, and the uniquely suited aspects of the institutional environment. ?
