Neurological disease represents a tremendous personal burden to patients and families and financial burden to society. With our rapidly aging population, these burdens are estimated to increase dramatically in the coming decades. Conventional research efforts focus on identifying the distinct etiologies and developing disease-specific treatments for debilitating neurological disorders such as Alzheimer's Disease, stroke, Multiple Sclerosis, glaucoma, and peripheral neuropathy. As an alternative, we are focusing on a shared feature of these disorders-the degeneration of injured axons. We hypothesize that a common, evolutionarily conserved cell biological pathway triggers axonal degeneration, and that inhibiting this pathway will preserve axonal connections and serve as an effective treatment in these and other neurological diseases. To test this hypothesis, we are developing an innovative, high-throughput set of tools for the genome-wide identification and characterization of proteins and pathways involved in axonal degradation using both Drosophila and primary mouse neuronal systems. By focusing on candidates validated in both systems, we anticipate elucidating this critical program. We will identifying a host of proteins, some of which are likely to represent reasonable pharmacological targets that could be modulated in order to block or delay axonal degeneration. If successful, this proposal will stimulate the development of treatments for a wide range of devastating neurological disorders.
This research is relevant to public health because it will identify potential therapeutic targets for a host of debilitating neurological disorders. Axonal degeneration is a shared component of many neurological disorders including neurodegenerative diseases like Alzheimer's, Parkinson's and Multiple Sclerosis, and it is also an important aspect of hereditary, chemotherapy-induced and diabetic neuropathies, stroke, and glaucoma. Defining the molecular mechanisms of the axonal self-destructive pathway will identify novel therapeutic candidates for these disorders where morbidity is largely caused by axonal dysfunction.
| Sasaki, Yo; Margolin, Zachary; Borgo, Benjamin et al. (2015) Characterization of Leber Congenital Amaurosis-associated NMNAT1 Mutants. J Biol Chem 290:17228-38 |
| Gerdts, Josiah; Brace, E J; Sasaki, Yo et al. (2015) SARM1 activation triggers axon degeneration locally via NAD? destruction. Science 348:453-7 |
| Summers, Daniel W; DiAntonio, Aaron; Milbrandt, Jeffrey (2014) Mitochondrial dysfunction induces Sarm1-dependent cell death in sensory neurons. J Neurosci 34:9338-50 |
| Babetto, Elisabetta; Beirowski, Bogdan; Russler, Emilie V et al. (2013) The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction. Cell Rep 3:1422-9 |
| Scott, Barbara; Sun, Chun-Ling; Mao, Xianrong et al. (2013) Role of oxygen consumption in hypoxia protection by translation factor depletion. J Exp Biol 216:2283-92 |
| Gerdts, Josiah; Summers, Daniel W; Sasaki, Yo et al. (2013) Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J Neurosci 33:13569-80 |
| Bhattacharya, Martha R C; Gerdts, Josiah; Naylor, Sarah A et al. (2012) A model of toxic neuropathy in Drosophila reveals a role for MORN4 in promoting axonal degeneration. J Neurosci 32:5054-61 |
