Studies of SARM1 uncover similarities between immune and neuronal responses to danger.

Toll-interleukin-1 receptor (TIR) domain-containing proteins are best known as critical players in vertebrate immune defense against pathogens. Four of the five members of this family are required for the activation of immune cells downstream of the engagement of Toll-like receptors (TLRs) by microbial molecules. Mice deficient in any one of these four molecules show greatly enhanced susceptibility to specific classes of pathogens. However, the physiological function of the fifth mammalian protein, sterile alpha and TIR motif-containing 1 [SARM1, also known as myeloid differentiation marker 88-5 (MyD88-5)], has remained elusive. Now, the study of the SARM1 reporter and SARM1-deficient mice has uncovered an unanticipated function of this molecule in the regulation of neuronal survival in response to metabolic stress. Together with pioneering observations on the functions of TIR-1, the worm ortholog of SARM1, and other reports on the role of TLRs in neuronal development and responses to injury in mammals, these exciting results suggest that further studies of SARM1-deficient animals may uncover unexpected similarities between the ways in which neurons and immune cells sense and respond to danger.