Protein Aggregation and Modification in Neurodegeneration

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DESCRIPTION (provided by applicant): I have spent all of my professional training involved in the study of neurodegenerative disease with an early background in Parkinson's disease, and a purposefully sought postdoctoral position in the laboratory of Dr. Dennis Selkoe at the Center for Neurologic Disease (CND). I have begun an independent line of research clearly distinct from that of my mentor, and seek NIH support to further these studies under the continued guidance of Dr. Selkoe. I have chosen Dr. Selkoe as my mentor because: a) he is a recognized leader in the field of neurodegenerative disease-related cell biology with a remarkable history of training successful, independent researchers early in their careers, b) the Selkoe laboratory continues to provide a stimulating environment focused on issues of protein aggregation, protein-protein interactions in neurodegenerative disease and cell signaling and c) the support of the CND, and of Dr. Selkoe in particular, demonstrate a strong commitment to my continued development as an independent investigator. The CND is an ideal environment to conduct basic research in neurodegeneration, as it is the sole focus of its 14 principal investigators. Furthermore, there is liberal access to the vast resources of the Harvard Center for Neurodegenerative Disease and Repair, as well as collaborative and training opportunities throughout Harvard Medical School. My preliminary data demonstrate that the neurotransmitter dopamine (DA) itself adversely affects Parkin function, causing aggregation and oligomerization of the Parkin protein and inactivation of its E3 ligase activity. These data suggest that DA may contribute to a partial Parkin loss of function in idiopathic PD. The focus of the first 2 Aims of this proposal is to characterize the selective vulnerability of Parkin to modification by DA and determine whether this post-translational modification can be found in human brain. The training goals of this K01 application are to expand my expertise to include protein chemistry and mass spectrometric analyses, relevant to the growing interest in post-translational modification (i.e., Parkin) and cleavage (i.e., a-synuclein) of proteins in neurological disease. Additionally, I propose to gain expertise in the study of appptosis and the role mitochondria play in cell death under the tutelage of Dr. Stanley Korsmeyer. This collaboration is directly relevant to the model of dopamine-induced Parkin deficiency outlined herein, and would provide a world-class training experience in the execution of Aim 3: to determine whether Parkin deficiency promotes mitochondria-induced apoptosis.