The objective is to identify compounds that will improve axonal transport in neurons carrying the mutation. The compounds we will survey are ones with a known mechanism of action and thus will identify cellular signaling pathways with the potential to overcome the transport deficits. These pathways are likely to include drug‐able targets that could ultimately serve as a point of therapeutic intervention. Strategy: Cultured neurons from the sacsin knockout mouse will be employed in this project. Identifying compounds that improve mitochondrial transport in these cells will have four component aims. The first will be to examine transport in detail in multiple neuronal cell types and developmental stages in order to find a suitable system for characterization and screening. The second stage will involve a detailed characterization of the transport defect to determine if it is indeed mitochondrion‐specific or influences multiple cargoes and whether it alters both anterograde and retrograde movement. The third stage will take advantage of a medium‐throughput compound screen currently being performed in my laboratory to identify compounds that alter mitochondrial transport in wildtype hippocampal neurons. “Hits” identified in this screen that increase transport will be tested on the sacsin mutant neurons to see if they can restore normal transport. In the fourth stage a medium‐throughput screen for compounds of known mode of action will be conducted using the sacsin mutant neurons. The power of this latter approach lies in its choice of endpoint. By using mitochondrial motility as an endpoint, compounds of value can be recognized regardless of whether they act directly and solely on mitochondria, or act via amelioration of a change in the cytoskeleton
Duration: one year
Grant: $96,568
Contact:
Dr. Thomas L. Schwarz
Dr. Thomas L. Schwarz, Professor, F.M. Kirby Neurobiology Center Children’s Hospital, Boston and Dept.of Neurobiology
Harvard Medical School CLSB 12-130, 3 Blackfan Street, Boston, MA 02115
Tel:(617)-919-2219 (office) or (617)-919-2264 (lab)