Distinct developmental and degenerative functions of SARM1 require NAD+ hydrolase activity

SARM1 is the founding member of the TIR-domain family of NAD+ hydrolases and the central executioner of pathological axon degeneration. SARM1-dependent degeneration requires NAD+ hydrolysis. Prior to the discovery that SARM1 is an enzyme, SARM1 was studied as a TIR-domain adaptor protein with non-degenerative signaling roles in innate immunity and invertebrate neurodevelopment, including at the Drosophila neuromuscular junction (NMJ). Here we explore whether the NADase activity of SARM1 also contributes to developmental signaling. We developed transgenic Drosophila lines that express SARM1 variants with normal, deficient, and enhanced NADase activity and tested their function in NMJ development. We find that NMJ overgrowth scales with the amount of NADase activity, suggesting an instructive role for NAD+ hydrolysis in this developmental signaling pathway. While degenerative and developmental SARM1 signaling share a requirement for NAD+ hydrolysis, we demonstrate that these signals use distinct upstream and downstream mechanisms. These results identify SARM1-dependent NAD+ hydrolysis as a heretofore unappreciated component of developmental signaling. SARM1 now joins sirtuins and Parps as enzymes that regulate signal transduction pathways via mechanisms that involve NAD+ cleavage, greatly expanding the potential scope of SARM1 TIR NADase functions

Exploring the Role of Mutant-Huntingtin in Early Transcription Dysregulation of Huntington\u27s Disease

From the Washington University Office of Undergraduate Research Digest (WUURD), Vol. 13, 05-01-2018. Published by the Office of Undergraduate Research. Joy Zalis Kiefer, Director of Undergraduate Research and Associate Dean in the College of Arts & Sciences; Lindsey Paunovich, Editor; Helen Human, Programs Manager and Assistant Dean in the College of Arts and Sciences Mentor(s): Hiroko Yan

The role of substrate in unmasking oxyl character in oxomanganese complexes: the key to selectivity?

The reaction profile for sulfide oxidation by formally Mn(v)=O species depends critically on the electronic structure of the isolated oxidant. In cases where the ground state has dominant oxyl radical character, the oxidation occurs in sequential one-electron steps, the first of which is barrierless. In contrast, if the oxyl radical character is 'masked' in the ground state by electron transfer from either the metal or the porphyrin co-ligand, the interaction between oxidant and substrate is repulsive at large separations, only becoming attractive when the incoming nucleophile approaches close enough to drive an electron out of oxide p pi manifold, thereby 'unmasking' the oxyl radical. The shape of the repulsive wall at long range will depend on the properties of both oxidant and substrate, offering the potential for substrate discrimination that is one of the most remarkable properties of the oxygen evolving complex. The electronic properties of the oxidant depend critically on the identity of the axial co-ligand, but also on the chosen density functional. As a result, hybrid and non-hybrid functionals give very different qualitative descriptions of the oxidation reaction