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Yo Sasaki, Takashi Nakagawa, Xianrong Mao, Aaron DiAntonio, Jeffrey Milbrandt
Overexpression of the NAD(+) biosynthetic enzyme NMNAT1 leads to preservation of injured axons. While increased NAD(+) or decreased NMN levels are thought to be critical to this process, the mechanism(s) of this axon protection remain obscure. Using steady-state and flux analysis of NAD(+) metabolites in healthy and injured mouse dorsal root ganglion axons, we find that rather than altering NAD(+) synthesis, NMNAT1 instead blocks the injury-induced, SARM1-dependent NAD(+) consumption that is central to axon degeneration...
October 13, 2016: ELife
Daniel W Summers, Daniel A Gibson, Aaron DiAntonio, Jeffrey Milbrandt
Axon injury in response to trauma or disease stimulates a self-destruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
Matthew J Geden, Mohanish Deshmukh
Axon degeneration is an essential part of development, plasticity, and injury response and has been primarily studied in mammalian models in three contexts: 1) Axotomy-induced Wallerian degeneration, 2) Apoptosis-induced axon degeneration (axon apoptosis), and 3) Axon pruning. These three contexts dictate engagement of distinct pathways for axon degeneration. Recent advances have identified the importance of SARM1, NMNATs, NAD+ depletion, and MAPK signaling in axotomy-induced Wallerian degeneration. Interestingly, apoptosis-induced axon degeneration and axon pruning have many shared mechanisms both in signaling (e...
August 2016: Current Opinion in Neurobiology
Biao Chang, Qi Quan, Shibi Lu, Yu Wang, Jiang Peng
Axonal degeneration is an early hallmark of nerve injury and many neurodegenerative diseases. The discovery of the Wallerian degeneration slow mutant mouse, in which axonal degeneration is delayed, revealed that Wallerian degeneration is an active progress and thereby illuminated the mechanisms underlying axonal degeneration. Nicotinamide mononucleotide adenylyltransferase 2 and sterile alpha and armadillo motif-containing protein 1 play essential roles in the maintenance of axon integrity by regulating the level of nicotinamide adenine dinucleotide, which seems to be the key molecule involved in the maintenance of axonal health...
August 2016: European Journal of Neuroscience
Nils Henninger, James Bouley, Elif M Sikoglu, Jiyan An, Constance M Moore, Jean A King, Robert Bowser, Marc R Freeman, Robert H Brown
Axonal degeneration is a critical, early event in many acute and chronic neurological disorders. It has been consistently observed after traumatic brain injury, but whether axon degeneration is a driver of traumatic brain injury remains unclear. Molecular pathways underlying the pathology of traumatic brain injury have not been defined, and there is no efficacious treatment for traumatic brain injury. Here we show that mice lacking the mouse Toll receptor adaptor Sarm1 (sterile α/Armadillo/Toll-Interleukin receptor homology domain protein) gene, a key mediator of Wallerian degeneration, demonstrate multiple improved traumatic brain injury-associated phenotypes after injury in a closed-head mild traumatic brain injury model...
April 2016: Brain: a Journal of Neurology
Josiah Gerdts, Daniel W Summers, Jeffrey Milbrandt, Aaron DiAntonio
Wallerian axon degeneration is a form of programmed subcellular death that promotes axon breakdown in disease and injury. Active degeneration requires SARM1 and MAP kinases, including DLK, while the NAD+ synthetic enzyme NMNAT2 prevents degeneration. New studies reveal that these pathways cooperate in a locally mediated axon destruction program, with NAD+ metabolism playing a central role. Here, we review the biology of Wallerian-type axon degeneration and discuss the most recent findings, with special emphasis on critical signaling events and their potential as therapeutic targets for axonopathy...
February 3, 2016: Neuron
Michel Brahic, Luc Bousset, Gregor Bieri, Ronald Melki, Aaron D Gitler
Accruing evidence suggests that prion-like behavior of fibrillar forms of α-synuclein, β-amyloid peptide and mutant huntingtin are responsible for the spread of the lesions that characterize Parkinson disease, Alzheimer disease and Huntington disease, respectively. It is unknown whether these distinct protein assemblies are transported within and between neurons by similar or distinct mechanisms. It is also unclear if neuronal death or injury is required for neuron-to-neuron transfer. To address these questions, we used mouse primary cortical neurons grown in microfluidic devices to measure the amounts of α-synuclein, Aβ42 and HTTExon1 fibrils transported by axons in both directions (anterograde and retrograde), as well as to examine the mechanism of their release from axons after anterograde transport...
April 2016: Acta Neuropathologica
Andrea Loreto, Michele Di Stefano, Martin Gering, Laura Conforti
Axon injury leads to rapid depletion of NAD-biosynthetic enzyme NMNAT2 and high levels of its substrate, NMN. We proposed a key role for NMN in Wallerian degeneration but downstream events and their relationship to other mediators remain unclear. Here, we show, in vitro and in vivo, that axotomy leads to a late increase in intra-axonal Ca(2+), abolished by pharmacological or genetic reduction of NMN levels. NMN requires the pro-degenerative protein SARM1 to stimulate Ca(2+) influx and axon degeneration. While inhibition of NMN synthesis and SARM1 deletion block Ca(2+) rise and preserve axonal integrity, they fail to prevent early mitochondrial dynamic changes...
December 22, 2015: Cell Reports
Piyali Mukherjee, Clayton W Winkler, Katherine G Taylor, Tyson A Woods, Vinod Nair, Burhan A Khan, Karin E Peterson
Neuronal apoptosis is a key aspect of many different neurologic diseases, but the mechanisms remain unresolved. Recent studies have suggested a mechanism of innate immune-induced neuronal apoptosis through the stimulation of endosomal TLRs in neurons. TLRs are stimulated both by pathogen-associated molecular patterns as well as by damage-associated molecular patterns, including microRNAs released by damaged neurons. In the present study, we identified the mechanism responsible for TLR7/TLR9-mediated neuronal apoptosis...
November 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Julie Vérièpe, Lucresse Fossouo, J Alex Parker
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease thought to employ cell non-autonomous mechanisms where neuronal injury engages immune responses to influence disease progression. Here we show that the expression of mutant proteins causative for ALS in Caenorhabditis elegans motor neurons induces an innate immune response via TIR-1/Sarm1. Loss of function mutations in tir-1, associated downstream kinases, and the transcription factor atf-7 all suppress motor neuron degeneration. The neurosecretory proteins UNC-13 and UNC-31 are required for induction of the immune response as well as the degeneration of motor neurons...
2015: Nature Communications
Van Hieu Dong, Pang-Yan Tu, Pei-Chun Tsai, Yi-Hsin Lin, Hsiu-Luan Chang, Tsun-Yung Kuo, Ming-Tang Chiou, Chao-Nan Lin, Wen-Bin Chung
Pigs co-infected with porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) have been shown to develop more severe diseases than pigs infected with PRRSV or PCV2 only. The underlying interaction mechanisms between the two viruses in developing the disease are unclear. The present study investigates the mRNA expression of Toll-like receptor (TLR) signaling-related molecules in peripheral blood mononuclear cells from pigs infected with PRRSV or PCV2 or both. The mRNA expression levels were determined by quantitative real-time RT-PCR...
August 2015: Research in Veterinary Science
Josiah Gerdts, E J Brace, Yo Sasaki, Aaron DiAntonio, Jeffrey Milbrandt
Axon degeneration is an intrinsic self-destruction program that underlies axon loss during injury and disease. Sterile alpha and TIR motif-containing 1 (SARM1) protein is an essential mediator of axon degeneration. We report that SARM1 initiates a local destruction program involving rapid breakdown of nicotinamide adenine dinucleotide (NAD(+)) after injury. We used an engineered protease-sensitized SARM1 to demonstrate that SARM1 activity is required after axon injury to induce axon degeneration. Dimerization of the Toll-interleukin receptor (TIR) domain of SARM1 alone was sufficient to induce locally mediated axon degeneration...
April 24, 2015: Science
Jonathan Gilley, Giuseppe Orsomando, Isabel Nascimento-Ferreira, Michael P Coleman
SARM1 function and nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) loss both promote axon degeneration, but their relative relationship in the process is unknown. Here, we show that NMNAT2 loss and resultant changes to NMNAT metabolites occur in injured SARM1-deficient axons despite their delayed degeneration and that axon degeneration specifically induced by NMNAT2 depletion requires SARM1. Strikingly, SARM1 deficiency also corrects axon outgrowth in mice lacking NMNAT2, independently of NMNAT metabolites, preventing perinatal lethality...
March 31, 2015: Cell Reports
Jing Yang, Zhuhao Wu, Nicolas Renier, David J Simon, Kunihiro Uryu, David S Park, Peter A Greer, Cathy Tournier, Roger J Davis, Marc Tessier-Lavigne
Axonal death disrupts functional connectivity of neural circuits and is a critical feature of many neurodegenerative disorders. Pathological axon degeneration often occurs independently of known programmed death pathways, but the underlying molecular mechanisms remain largely unknown. Using traumatic injury as a model, we systematically investigate mitogen-activated protein kinase (MAPK) families and delineate a MAPK cascade that represents the early degenerative response to axonal injury. The adaptor protein Sarm1 is required for activation of this MAPK cascade, and this Sarm1-MAPK pathway disrupts axonal energy homeostasis, leading to ATP depletion before physical breakdown of damaged axons...
January 15, 2015: Cell
Shravan K Chintala, Nahrain Putris, Mason Geno
PURPOSE: To investigate whether activation of Toll-like receptor 3 (TLR3) promotes the degeneration of retinal ganglion cells (RGCs) by upregulating the protein levels of c-jun N-terminal kinase 3 (JNK3). METHODS: Toll-like receptor 3-specific activator, Poly(I:C) (polyinosinic-polycytidylic acid), or PBS was injected into the vitreous humor of Thy1-YFP mice. At 24, 48, and 72 hours after treatments, degeneration of RGCs was assessed by using antibodies against brain-specific homeobox/POU domain protein 3a (Brn3a)...
January 2015: Investigative Ophthalmology & Visual Science
Katharina Godzik, Michael P Coleman
The axon-protective Wallerian degeneration slow (WLD(S)) protein can ameliorate the decline in axonal ATP levels after neurite transection. Here, we tested the hypothesis that this effect is associated with maintenance of mitochondrial respiration and/or glycolysis. We used isolated neurites of superior cervical ganglion (SCG) cultures in the Seahorse XF-24 Metabolic Flux Analyser to determine mitochondrial respiration and glycolysis under different conditions. We observed that both mitochondrial respiration and glycolysis declined significantly during the latent phase of Wallerian degeneration...
April 2015: Journal of Molecular Neuroscience: MN
Nana Yan, Jianguo Su, Chunrong Yang, Youliang Rao, Xiaoli Feng, Quanyuan Wan, Chuzhao Lei
Sterile alpha and Toll/IL-1R motif containing 1 (SARM1) negatively regulates TRIF-dependent TLR signaling in mammals. However, its immune function remains unclear in teleost. Here, a grass carp Ctenopharyngodon idella SARM1 (CiSARM1) gene and its two novel splice variants (CiSARM1s1 and CiSARM1s2) were identified. CiSARM1s1 and CiSARM1s2 are generated by intron retention mechanism, and they only retain N-terminal HEAT/armadillo motifs. In C. idella kidney (CIK) cells, CiSARM1 and CiSARM1s1 are located in mitochondria, whereas CiSARM1s2 distributes in the whole cell...
January 2015: Developmental and Comparative Immunology
Helen M Crook-McMahon, Monika Oláhová, Emma L Button, Johnathan J Winter, Elizabeth A Veal
BACKGROUND: Phase 2 detoxification enzymes provide a vital defence against reactive oxygen species, including xenobiotic metabolites, which cause the oxidative damage involved in drug toxicity and many diseases. Hence, there is great interest in understanding how levels of these enzymes are regulated. CnC transcription factors, such as mammalian Nrf2, drive the expression of phase 2 enzymes and are activated as an important conserved response to oxidative stress and xenobiotics. For instance, the Caenorhabditis elegans Nrf2 orthologue, SKN-1, is activated in response to arsenite by the stress-activated p38-related kinase, PMK-1, leading to increased expression of phase 2 enzymes...
2014: BMC Biology
Daniel W Summers, Aaron DiAntonio, Jeffrey Milbrandt
Mitochondrial dysfunction is the underlying cause of many neurological disorders, including peripheral neuropathies. Mitochondria rely on a proton gradient to generate ATP and interfering with electron transport chain function can lead to the deleterious accumulation of reactive oxygen species (ROS). Notably, loss of mitochondrial potential precedes cellular demise in several programmed cell destruction pathways, including axons undergoing Wallerian degeneration. Here, we demonstrate that mitochondrial depolarization triggers axon degeneration and cell death in primary mouse sensory neurons...
July 9, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Hsin-Yu Liu, Chiung-Ya Chen, Yi-Ping Hsueh
The central nervous system is recognized as an immunoprivileged site because peripheral immune cells do not typically enter it. Microglial cells are thought to be the main immune cells in brain. However, recent reports have indicated that neurons express the key players of innate immunity, including Toll-like receptors (TLRs) and their adaptor proteins (Sarm1, Myd88, and Trif), and may produce cytokines in response to pathogen infection. In the absence of an immune challenge, neuronal TLRs can detect intrinsic danger signals and modulate neuronal morphology and function...
August 2014: Neuroscience Bulletin
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