Exploring hSARM1 Network Interactions

SARM1 (sterile α and HEAT/armadillo motif-containing protein) induces axonal degeneration after nerve injury and in other neuropathological conditions such as in bipolar/ photoreceptor cells. It also plays vital roles in innate immunity by regulating TLR and inflammasome mediated responses. The domain composition of human (h)SARM1 includes an N-terminal peptide, an ARM repeats region, two SAM and one TIR domain which mediate mitochondria targeting, autoinhibition, oligomerization and NADase activity respectively. In axon degeneration, SARM1 evokes NADase activity which depletes the key cellular metabolites NAD+ and generates ADPR. On the other hand, it is thought that direct TIR-TIR interactions between SARM1 and the innate immune transducer MyD88 (Myeloid differentiation factor 88) are required to achieve negative regulation of TLR signaling. In this research I study the interactions of hSARM1 with MyD88, and the possible effects of such interaction over the enzymatic activity of hSARM1 in axonal degeneration. To that end I use a variety of biochemical and cellular tools such as MST (microscale thermophoresis), NADase in-vitro measurements and cell viability assays. Complemented with structural-functional studies of hSARM1 complexed with MyD88 will greatly contribute to our understanding of hSARM1 regulation and role in innate immunity and would allow the development of new classes of drugs for the treatment of axonal degeneration.