Abstract
Wallerian axonal degeneration (WD) does not occur in the nematode C. elegans, in contrast to other model animals. However, WD depends on the NADase activity of SARM1, a protein that is also expressed in C. elegans (ceSARM/ceTIR-1). We hypothesized that differences in SARM between species might exist and account for the divergence in WD. We first show that expression of the human (h)SARM1, but not ceTIR-1, in C. elegans neurons is sufficient to confer axon degeneration after nerve injury. Next, we determined the cryoelectron microscopy structure of ceTIR-1 and found that, unlike hSARM1, which exists as an auto-inhibited ring octamer, ceTIR-1 forms a readily active 9-mer. Enzymatically, the NADase activity of ceTIR-1 is substantially weaker (10-fold higher Km) than that of hSARM1, and even when fully active, it falls short of consuming all cellular NAD+. Our experiments provide insight into the molecular mechanisms and evolution of SARM orthologs and WD across species.
| Original language | English |
|---|---|
| Article number | 113026 |
| Journal | Cell Reports |
| Volume | 42 |
| Issue number | 9 |
| DOIs | |
| State | Published - 26 Sep 2023 |
Bibliographical note
Publisher Copyright:© 2023 The Author(s)
Funding
We acknowledge the European Synchrotron Radiation Facility for provision of beam time on CM01 and thank the staff of beamline CM01 of ESRF and members of the Opatowsky lab for technical assistance. We thank Gershon Kunin for IT management and Dr. Moshe Goldsmith from the Weizmann institute for mass photometry measurements. This work was supported by funds from ISF grants nos. 1425/15 and 909/19, BSF grant no. 2019150, and ICRF grant 2022-2023 to Y.O. and NIH R01 NS094219 to M.H. Y.O. is a Katzir Professorial Chair of Biophysics. Y.O. and M. Hammarlund formulated the research plan and interpreted results. T.K. A.G. J.G.-H. C.F. H.D. R.S. M.W. R.Z. M.N.I. M. Hammarlund, M. Hons, and Y.O. designed and performed experiments and analyzed the data. M. Hammarlund supervised the C. elegans experiments, and C.F. and H.D. conducted them. Y.O. and M. Hammarlund wrote the manuscript with input from all authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. This work was supported by funds from ISF grants nos. 1425/15 and 909/19 , BSF grant no. 2019150 , and ICRF grant 2022-2023 to Y.O., and NIH R01 NS094219 to M.H. Y.O. is a Katzir Professorial Chair of Biophysics.
| Funders | Funder number |
|---|---|
| Gershon Kunin | |
| National Institutes of Health | R01 NS094219 |
| Israel Cancer Research Fund | 2022-2023 |
| Bloom's Syndrome Foundation | 2019150 |
| Iowa Science Foundation | 909/19, 1425/15 |
| European Synchrotron Radiation Facility |
Keywords
- C. elegans
- CP: Molecular biology
- CP: Neuroscience
- NAD metabolism
- SARM1
- TIR-1
- Wallerian degeneration
- axon
- cryo-EM
- neurodegeneration
- structural biology