A5046035395- Endoplasmic Reticulum Stress and Disease
- Immune Response and Inflammation
- NF-κB Signaling Pathways
- Sirtuins and Resveratrol in Medicine
- Mitochondrial Function and Pathology
- RNA regulation and disease
- Autophagy in Disease and Therapy
- Nerve injury and regeneration
- Signaling Pathways in Disease
- Calcium signaling and nucleotide metabolism
- Biochemical effects in animals
- Neuroinflammation and Neurodegeneration Mechanisms
- Genetics, Aging, and Longevity in Model Organisms
- Amyotrophic Lateral Sclerosis Research
- Antimicrobial Peptides and Activities
- RNA Research and Splicing
- Neuroscience and Neuropharmacology Research
- Medicinal Plants and Bioactive Compounds
- Genomics, phytochemicals, and oxidative stress
- Biochemical and Structural Characterization
- Alzheimer's disease research and treatments
- interferon and immune responses
- Nuclear Receptors and Signaling
- S100 Proteins and Annexins
- Cytokine Signaling Pathways and Interactions
Center for Neuro-Oncology
2021-2022
Washington University in St. Louis
2009-2022
Arkansas Cardiology
2002-2006
University of Arkansas for Medical Sciences
1998-2006
John L. McClellan Memorial Veterans Hospital
1999
Overexpression of the NAD+ biosynthetic enzyme NMNAT1 leads to preservation injured axons. While increased or decreased NMN levels are thought be critical this process, mechanism(s) axon protection remain obscure. Using steady-state and flux analysis metabolites in healthy mouse dorsal root ganglion axons, we find that rather than altering synthesis, instead blocks injury-induced, SARM1-dependent consumption is central degeneration.
Axonal degeneration is responsible for disease progression and accumulation of disability in many neurodegenerative conditions. The axonal degenerative process can generate a metastable pool damaged axons that remain structurally functionally viable but fated to degenerate the absence external intervention. SARM1, an NADase depletes energy stores upon activation, central driver evolutionarily conserved program degeneration. We identify potent selective small molecule isoquinoline inhibitor...
The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration therapeutic target for several neurodegenerative conditions. We show that potent inhibitor undergoes base exchange with the nicotinamide moiety adenine dinucleotide (NAD
Abstract Background In response to injury, neurons activate a program of organized axon self-destruction initiated by the NAD + hydrolase, SARM1. healthy SARM1 is autoinhibited, but single amino acid changes can abolish autoinhibition leading constitutively active enzymes that promote degeneration when expressed in cultured neurons. Methods To investigate whether naturally occurring human variants might disrupt and potentially contribute risk for neurodegenerative disease, we assayed...
Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection models disease, suggesting that inhibiting SARM1 a promising strategy to reduce pathological AxD. Unfortunately, no drugs exist target SARM1. We, therefore, developed dominant-negatives potently block cellular axotomy neuropathy. To assess efficacy vivo, we...
Significance Axon degeneration is an active program of subcellular self-destruction that drives pathology in the injured and diseased nervous system. SARM1 inducible NAD + hydrolase central executioner axon loss. In healthy axons, NADase autoinhibited. With injury or disease, this autoinhibition relieved depletes , inducing a metabolic crisis subsequent Here we combine peptide screening, cryo-electron microscopy, site-directed mutagenesis with analysis axonal metabolomics to define five...
Hypoxia is important in a wide range of biological processes, such as animal hibernation and cell survival, particularly relevant many diseases. The sensitivity cells organisms to hypoxic injury varies widely, but the molecular basis for this variation incompletely understood. Using forward genetic screens Caenorhabditis elegans, we isolated hypoxia-resistant reduction-of-function mutant rrt-1 that encodes an arginyl-transfer RNA (tRNA) synthetase, enzyme essential protein translation....
LEVELS of dehydroepiandrosterone (DHEA) and its sulfated derivative (DHEA-S) decline during aging reach even lower levels in Alzheimer's disease (AD). Previously published effects DHEA DHEA-S on unchallenged neuronal survival led us to test them an excitotoxicity paradigm. While protected hippocampal neurons against glutamate, little protection was observed with equivalent doses itself. This differential neuroprotection consistent the ability (but not DHEA) elevate a κB-dependent...
Prolonged cellular hypoxia results in energy failure and ultimately cell death. However, less-severe can induce a cytoprotective response termed hypoxic preconditioning (HP). The unfolded protein pathway (UPR) has been known for some time to respond regulate sensitivity; however, the role of UPR, if any, HP essentially unexplored. We have shown previously that sublethal exposure nematode Caenorhabditis elegans induces chaperone component UPR (L. L. Anderson, X. Mao, B. A. Scott, C. M....
Highlights•The neurotoxin 3-acetylpyridine is converted into a SARM1 allosteric activator•The binding site relatively promiscuous•SARM1 candidate mediator of environmental neurotoxicity•SARM1 agonists could be developed selective agents for neurolytic therapySummarySARM1 an inducible TIR-domain NAD+ hydrolase that mediates pathological axon degeneration. activated by increased ratio NMN to NAD+, which competes activating site. When binds, the TIR domain released from autoinhibition, its...
Abstract Sp‐family transcription factors (Sp1, Sp3 and Sp4) contain a zinc‐finger domain that binds to DNA sequences rich in G–C/T. As assayed by RT‐PCR analysis of mRNA, western‐blot analysis, immunofluorescence, antibody‐dependent “supershift” DNA‐binding assays, the prominent cerebral neurons were identified as Sp4. By contrast, glial cells found express Sp1 Sp3. We previously showed pattern G–C/T binding activity is rapidly specifically altered calcium influx accompanying activation...
In addition to their conventional G-C/T target sequences, Sp1 family transcription factors (Sp-factors) can interact with a subset of the sequences for NFκB. Due low level bona fide NFκB activity in most resting cells, this interaction between Sp-factors and κB-sites could play important roles cell function. Here we used mutagenesis canonical κB element from immunoglobulin HIV promoters identify GC-rich at each end required Sp-factor targeting. Through screening multiple elements, sequence...
The sensitivity of an organism to hypoxic injury varies widely across species and among cell types. However, a systematic description the determinants metazoan is lacking. Toward this end, we screened whole-genome RNAi library for genes that promote in Caenorhabditis elegans. knockdown 198 conferred invariant hypoxia-resistant phenotype (Hyp-r). Eighty-six per cent these hyp had strong homologs other organisms, 73 with human reciprocal orthologs. were distributed multiple functional...
Gain-of-function mutations in the mouse nicotinamide mononucleotide adenylyltransferase type 1 (Nmnat1) produce two remarkable phenotypes: protection against traumatic axonal degeneration and reduced hypoxic brain injury. Despite intensive efforts, mechanism of Nmnat1 cytoprotection remains elusive. To develop a new model to define this mechanism, we heterologously expressed non-nuclear-localized gain-of-function mutant gene (m-nonN-Nmnat1) nematode Caenorhabditis elegans show that it...
SARM1 is the founding member of TIR-domain family NAD+ hydrolases and central executioner pathological axon degeneration. SARM1-dependent degeneration requires hydrolysis. Prior to discovery that an enzyme, was studied as a adaptor protein with non-degenerative signaling roles in innate immunity invertebrate neurodevelopment, including at Drosophila neuromuscular junction (NMJ). Here we explore whether NADase activity also contributes developmental signaling. We developed transgenic lines...
Neurons contain a protein factor capable of binding DNA elements normally bound by the transcription NF-κB. However, several lines evidence suggest that this neuronal κB-binding (NKBF) is not bona fide We have identified NKBF from cultures neocortical neurons as complex containing proteins related to Sp1. This was antibodies Sp1, Sp3, and Sp4 competed an NF-κB element oligonucleotide Sp1-binding site. Sp1 detected abundant in nuclei migrated electrophoretic mobility shift assays at position...
Summary Reduction of protein synthesis has been associated with resistance to hypoxic cell death. Which components the translation machinery control sensitivity and precise mechanism not systematically investigated although a reduction in oxygen consumption widely assumed be mechanism. Using genetic reagents C. elegans, we examined effect on organismal survival after hypoxia knockdown ten factors functioning at three principal steps translation. Reduction-of-function all significantly...
Abstract In response to injury, neurons activate a program of organized axon self-destruction initiated by the NAD + hydrolase SARM1. healthy SARM1 is autoinhibited, but single amino acid changes can abolish autoinhibition leading constitutively-active enzymes that promote degeneration when expressed in cultured neurons. To investigate whether naturally-occurring human variants might similarly disrupt and potentially contribute risk for neurodegenerative disease, we assayed enzymatic...
The control of NFκB in CNS neurons appears to differ from that other cell types. Studies have reported induction neuronal cultures and immunostaining vivo, but others consistently detected little or no transcriptional activation by brain neurons. To test if lack some component the signal transduction system for activation, we transfected cortical with several members this signaling along a luciferase-based NFκB-reporter plasmid; RelA was cotransfected conditions. No pathway permissive...