SARM1 is responsible for calpain-dependent dendrite degeneration in mouse hippocampal neurons

Sterile alpha and TIR motif containing 1 (SARM1) is a critical regulator of axon degeneration that acts through hydrolysis of NAD+ following injury. Recent work has defined the mechanisms underlying SARM1’s catalytic activity and advanced our understanding of SARM1 function in axons, yet the role of SARM1 signaling in other compartments of neurons is still not well understood. Here we show in cultured hippocampal neurons that endogenous SARM1 is present in axons, dendrites and cell bodies and that direct activation of SARM1 by the neurotoxin Vacor causes not just axon degeneration, but degeneration of all neuronal compartments. In contrast to the axon degeneration pathway defined in dorsal root ganglia (DRGs), SARM1-dependent hippocampal axon degeneration in vitro is not sensitive to calpain inhibition whereas dendrite degeneration downstream of SARM1 is calpain-dependent in this cell type. This data indicates SARM1 plays a critical role in neurodegeneration outside of axons and elucidates divergent pathways leading to degeneration in hippocampal axons and dendrites.

[1]  J. Gilley,et al.  NMN: The NAD precursor at the intersection between axon degeneration and anti-ageing therapies , 2023, Neuroscience Research.

[2]  J. Milbrandt,et al.  Shared TIR enzymatic functions regulate cell death and immunity across the tree of life , 2022, Science.

[3]  P. Thompson,et al.  The chemical biology of NAD+ regulation in axon degeneration. , 2022, Current opinion in chemical biology.

[4]  Labchan Rajbhandari,et al.  Protective effects of NAMPT or MAPK inhibitors and NaR on Wallerian degeneration of mammalian axons , 2022, Neurobiology of Disease.

[5]  Yang Cai,et al.  A Conformation-specific Nanobody Targeting the NMN-activated State of SARM1 , 2022, bioRxiv.

[6]  A. Sarkar,et al.  Phagocytosis and self-destruction break down dendrites of Drosophila sensory neurons at distinct steps of Wallerian degeneration , 2022, Proceedings of the National Academy of Sciences.

[7]  J. Milbrandt,et al.  Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN , 2021, The Journal of cell biology.

[8]  Yong Q. Zhang,et al.  The calcium-dependent protease calpain in neuronal remodeling and neurodegeneration , 2021, Trends in Neurosciences.

[9]  J. Milbrandt,et al.  Live imaging reveals the cellular events downstream of SARM1 activation , 2021, bioRxiv.

[10]  L. Hartley-Tassell,et al.  SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration , 2021, Neuron.

[11]  Yang Cai,et al.  Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate , 2021, bioRxiv.

[12]  A. Hoke,et al.  Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation , 2020, Scientific Reports.

[13]  Y. Shkolnisky,et al.  Structural basis for SARM1 inhibition and activation under energetic stress , 2020, eLife.

[14]  Q. Chang,et al.  The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1 , 2020, Nature.

[15]  A. Yaron,et al.  The Structural Basis for SARM1 Inhibition, and Activation Under Energetic Stress , 2020, bioRxiv.

[16]  Sean P. Brown,et al.  Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1. , 2020, Cell reports.

[17]  A. Höke,et al.  Programmed axon degeneration: from mouse to mechanism to medicine , 2020, Nature Reviews Neuroscience.

[18]  T. Engber,et al.  Axons Matter: The Promise of Treating Neurodegenerative Disorders by Targeting SARM1-Mediated Axonal Degeneration. , 2020, Trends in pharmacological sciences.

[19]  T. Engber,et al.  cADPR is a gene dosage-sensitive biomarker of SARM1 activity in healthy, compromised, and degenerating axons , 2020, Experimental Neurology.

[20]  P. Thompson,et al.  Initial Kinetic Characterization of Sterile Alpha and Toll/Interleukin Receptor Motif-Containing Protein 1. , 2020, Biochemistry.

[21]  Weili Tian,et al.  Systemic loss of Sarm1 protects Schwann cells from chemotoxicity by delaying axon degeneration , 2020, Communications Biology.

[22]  Hon Cheung Lee,et al.  Resolving the topological enigma in Ca2+ signaling by cyclic ADP-ribose and NAADP , 2019, The Journal of Biological Chemistry.

[23]  Bostjan Kobe,et al.  NAD+ cleavage activity by animal and plant TIR domains in cell death pathways , 2019, Science.

[24]  A. Whitworth,et al.  Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration , 2019, Neurobiology of Disease.

[25]  Zhengshuang Xu,et al.  A Cell-Permeant Mimetic of NMN Activates SARM1 to Produce Cyclic ADP-Ribose and Induce Non-apoptotic Cell Death , 2019, iScience.

[26]  G. Bartolucci,et al.  Identification of the Nicotinamide Salvage Pathway as a New Toxification Route for Antimetabolites. , 2018, Cell chemical biology.

[27]  J. Milbrandt,et al.  The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration , 2017, Neuron.

[28]  Kevin W. Eliceiri,et al.  ImageJ2: ImageJ for the next generation of scientific image data , 2017, BMC Bioinformatics.

[29]  R. Menna-Barreto,et al.  Why calpain inhibitors are interesting leading compounds to search for new therapeutic options to treat leishmaniasis? , 2016, Parasitology.

[30]  H. Sorimachi,et al.  Calpain research for drug discovery: challenges and potential , 2016, Nature Reviews Drug Discovery.

[31]  J. Milbrandt,et al.  NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion , 2016, eLife.

[32]  J. Milbrandt,et al.  Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism , 2016, Neuron.

[33]  M. Gering,et al.  Wallerian Degeneration Is Executed by an NMN-SARM1-Dependent Late Ca(2+) Influx but Only Modestly Influenced by Mitochondria. , 2015, Cell reports.

[34]  M. Tessier-Lavigne,et al.  Live Imaging of Calcium Dynamics during Axon Degeneration Reveals Two Functionally Distinct Phases of Calcium Influx , 2015, The Journal of Neuroscience.

[35]  A. Guse.  Calcium mobilizing second messengers derived from NAD. , 2015, Biochimica et biophysica acta.

[36]  R. Ribchester,et al.  A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration , 2014, Cell Death and Differentiation.

[37]  J. Milbrandt,et al.  Mitochondrial Dysfunction Induces Sarm1-Dependent Cell Death in Sensory Neurons , 2014, The Journal of Neuroscience.

[38]  N. Renier,et al.  Regulation of Axon Degeneration after Injury and in Development by the Endogenous Calpain Inhibitor Calpastatin , 2013, Neuron.

[39]  Catherine A. Collins,et al.  Sodium and Potassium Currents Influence Wallerian Degeneration of Injured Drosophila Axons , 2013, The Journal of Neuroscience.

[40]  J. Milbrandt,et al.  Sarm1-Mediated Axon Degeneration Requires Both SAM and TIR Interactions , 2013, The Journal of Neuroscience.

[41]  R. Neumar,et al.  Calpains mediate axonal cytoskeleton disintegration during Wallerian degeneration , 2013, Neurobiology of Disease.

[42]  D. O'Leary,et al.  A Caspase Cascade Regulating Developmental Axon Degeneration , 2012, The Journal of Neuroscience.

[43]  Mary A. Logan,et al.  dSarm/Sarm1 Is Required for Activation of an Injury-Induced Axon Death Pathway , 2012, Science.

[44]  L. Zhang,et al.  Studies of the Synthesis of Nicotinamide Nucleoside and Nucleotide Analogues and Their Inhibitions Towards CD38 NADase. , 2012 .

[45]  Zhenjun Yang,et al.  Studies on the Synthesis of Nicotinamide Nucleoside and Nucleotide Analogues and Their Inhibitions towards CD38 NADase , 2011 .

[46]  M. Rolls,et al.  Dendrites Have a Rapid Program of Injury-Induced Degeneration That Is Molecularly Distinct from Developmental Pruning , 2011, The Journal of Neuroscience.

[47]  R. Ribchester,et al.  Targeting NMNAT1 to Axons and Synapses Transforms Its Neuroprotective Potency In Vivo , 2010, The Journal of Neuroscience.

[48]  J. Gilley,et al.  Endogenous Nmnat2 Is an Essential Survival Factor for Maintenance of Healthy Axons , 2010, PLoS biology.

[49]  J. Milbrandt,et al.  Transgenic Mice Expressing the Nmnat1 Protein Manifest Robust Delay in Axonal Degeneration In Vivo , 2009, The Journal of Neuroscience.

[50]  R. Ribchester,et al.  WldS protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice , 2009, The Journal of cell biology.

[51]  T. O'Connor,et al.  Neurite consolidation is an active process requiring constant repression of protrusive activity , 2009, The EMBO journal.

[52]  Q. Hogan,et al.  Contribution of Calcium Channel Subtypes to the Intracellular Calcium Signal in Sensory Neurons: The Effect of Injury , 2007, Anesthesiology.

[53]  H. Kobori,et al.  New Generation Calcium Channel Blockers in Hypertensive Treatment. , 2006, Current hypertension reviews.

[54]  J. Milbrandt,et al.  Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration , 2004, Science.

[55]  V. Perry,et al.  Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene , 2001, Nature Neuroscience.

[56]  J. Kocsis,et al.  Voltage-gated calcium currents in axotomized adult rat cutaneous afferent neurons. , 2000, Journal of neurophysiology.

[57]  Junying Yuan,et al.  Specific Cleavage of α-Fodrin during Fas- and Tumor Necrosis Factor-induced Apoptosis Is Mediated by an Interleukin-1β-converting Enzyme/Ced-3 Protease Distinct from the Poly(ADP-ribose) Polymerase Protease* , 1996, The Journal of Biological Chemistry.

[58]  V. Perry,et al.  Absence of Wallerian Degeneration does not Hinder Regeneration in Peripheral Nerve , 1989, The European journal of neuroscience.

[59]  T. Tsujinaka,et al.  Synthesis of a new cell penetrating calpain inhibitor (calpeptin). , 1988, Biochemical and biophysical research communications.

[60]  P. LeWitt.  The neurotoxicity of the rat poison vacor. A clinical study of 12 cases. , 1980, The New England journal of medicine.

[61]  J. Geddes,et al.  through Increased Mitochondrial Flux and Enhanced Mitochondrial Ca 2+ Buffering , 2012 .

[62]  J. Mandell,et al.  Compartmentation of alpha-internexin and neurofilament triplet proteins in cultured hippocampal neurons , 1996, Journal of neurocytology.

[63]  D. Spyker,et al.  Diabetes mellitus associated with autonomic and peripheral neuropathy after Vacor rodenticide poisoning: a review. , 1981, Clinical toxicology.