Axons use a conserved program to actively drive their own destruction after injury. Axon degeneration is present in many neurological disorders and an axon death program could be a major pharmaceutical target to preserve neuronal function. This intrinsic signaling cascade activates pro-degenerative dSarm/Sarm1, rapidly depletes axonal stores of NAD+, and terminates in cytoskeletal breakdown. Conversely, loss of dSarm/Sarm1, maintenance of NAD+ levels or its biosynthetic enzyme Nmnat, result in long-term morphological perseveration of severed axons. Exactly how dSarm/Sarm1 and loss of NAD+ execute axon death remains poorly defined.
We sought to uncover novel regulators of axon death and maintenance by performing a deficiency screen and a forward genetic mutagenesis screen in axotomized Drosophila wing sensory neurons. We identified a BTB domain protein enriched in neurons, we named Axundead (Axed), which is specifically required for axon death. Severed axons harboring loss of function mutations in axed, similar to dSarm mutants, remain preserved for 50 days post axotomy. Spontaneous neurodegeneration induced by activated dSarm or dNmnat depletion are both suppressed in axed mutants, but not in dSarm mutant alleles. Additionally, severed axed mutant axons also expressing activated dSarm or lacking Nmnat are preserved. These results indicate that dSarm acts upstream of dNmnat loss, and both events precede essential Axed function and axon destruction. Thus, the axon death pathway converges on Axed function.
| Identifer | oai:union.ndltd.org:umassmed.edu/oai:escholarship.umassmed.edu:gsbs_diss-1903 |
| Date | 31 March 2017 |
| Creators | Burdett, Thomas C. |
| Publisher | eScholarship@UMassChan |
| Source Sets | University of Massachusetts Medical School |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Morningside Graduate School of Biomedical Sciences Dissertations and Theses |
| Rights | Licensed under a Creative Commons license, http://creativecommons.org/licenses/by-nc/4.0/ |
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