NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR

Cell Metabolism, Год журнала: 2017, Номер 27(3), С. 513 - 528

Опубликована: Дек. 14, 2017

Язык: Английский

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The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD + Cleavage Activity that Promotes Pathological Axonal Degeneration

Neuron, Год журнала: 2017, Номер 93(6), С. 1334 - 1343.e5

Опубликована: Март 1, 2017

Язык: Английский

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NAD ⁺ cleavage activity by animal and plant TIR domains in cell death pathways

Science, Год журнала: 2019, Номер 365(6455), С. 793 - 799

Опубликована: Авг. 23, 2019

NAD depletion as pathogen response One way that plants respond to infection is by sacrificing the infected cells. The nucleotide-binding leucine-rich repeat immune receptors responsible for this hypersensitive carry Toll/interleukin-1 receptor (TIR) domains. In two papers, Horsefield et al. and Wan report these TIR domains cleave metabolic cofactor nicotinamide adenine dinucleotide (NAD + ) part of their cell-death signaling in pathogens. Similar links mammalian TIR-containing proteins during Wallerian degeneration neurons. Science , issue p. 793 799

Язык: Английский

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Macrophage biology in the peripheral nervous system after injury

Progress in Neurobiology, Год журнала: 2018, Номер 173, С. 102 - 121

Опубликована: Дек. 21, 2018

Язык: Английский

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The etiology of Bell’s palsy: a review

Journal of Neurology, Год журнала: 2019, Номер 267(7), С. 1896 - 1905

Опубликована: Март 28, 2019

Bell's palsy is the most common condition involving a rapid and unilateral onset of peripheral paresis/paralysis seventh cranial nerve. It affects 11.5–53.3 per 100,000 individuals year across different populations. health issue causing concern has an extremely negative effect on both patients their families. Therefore, diagnosis prompt cause determination are key for early treatment. However, etiology unclear, this its Thus, it critical to determine causes so that targeted treatment approaches can be developed employed. This article reviews literature examines possible etiologies disorder. also suggests idiopathic facial based exclusion often made five factors including anatomical structure, viral infection, ischemia, inflammation, cold stimulation responsivity.

Язык: Английский

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Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice

Brain, Год журнала: 2016, Номер 139(12), С. 3092 - 3108

Опубликована: Окт. 25, 2016

Peripheral polyneuropathy is a common and dose-limiting side effect of many important chemotherapeutic agents. Most such neuropathies are characterized by early axonal degeneration, yet therapies that inhibit this destruction process do not currently exist. Recently, we others discovered genetic deletion SARM1 (sterile alpha TIR motif containing protein 1) dramatically protects axons from degeneration after axotomy in mice. This finding fuels hope inhibition or its downstream components can be used therapeutically patients threatened loss. However, axon loss most neuropathies, including chemotherapy-induced peripheral neuropathy, the result subacute/chronic processes may regulated differently than acute, one time insult axotomy. Here evaluate if decreases mouse model neuropathy induced agent vincristine. In wild-type mice, 4 weeks twice-weekly intraperitoneal injections 1.5 mg/kg vincristine cause pronounced mechanical heat hyperalgesia, significant decrease tail compound nerve action potential amplitude, intraepidermal fibres myelinated both distal sural nerves toe. Neither proximal nor motor tibial exhibit These findings consistent with development distal, sensory predominant mimics vincristine-induced humans. Using same regimen treatment knockout hyperalgesia blocked amplitude prevented. Moreover, mice lose unmyelinated skin toe Hence, blocks Our results reveal occurs via mediated pathway, blocking pathway prevents polyneuropathy. findings, conjunction previous studies traumatic brain injury, establish as central determinant fundamental activated diverse insults. We suggest targeting effectors viable therapeutic option to prevent possibly other polyneuropathies.

Язык: Английский

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TIR Domain Proteins Are an Ancient Family of NAD+-Consuming Enzymes

Current Biology, Год журнала: 2018, Номер 28(3), С. 421 - 430.e4

Опубликована: Янв. 25, 2018

Язык: Английский

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The Axon-Myelin Unit in Development and Degenerative Disease

Frontiers in Neuroscience, Год журнала: 2018, Номер 12

Опубликована: Июль 11, 2018

Axons are electrically excitable, cable-like neuronal processes that relay information between neurons within the nervous system and peripheral target tissues. In central systems, most axons over a critical diameter enwrapped by myelin, which reduces internodal membrane capacitance facilitates rapid conduction of electrical impulses. The spirally wrapped myelin sheath, is an evolutionary specialisation vertebrates, produced oligodendrocytes Schwann cells; in mammals myelination occurs during postnatal development after have established connection with their targets. Myelin covers vast majority axonal surface, influencing axon's physical shape, localisation molecules on its composition extracellular fluid (in periaxonal space) immerses it. unique architecture myelinated axon, crucial to function as conduit long distances, renders it particularly susceptible injury confers specific survival maintenance requirements. Moreover, myelinating cells play fundamental role support, at least part providing metabolic substrates underlying axon fuel energy this review we will describe normal morphology, ultrastructure axons, discuss how these change following disease, or experimental perturbation, particular focus cell plays shaping supporting axon.

Язык: Английский

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A Mechanistic Understanding of Axon Degeneration in Chemotherapy-Induced Peripheral Neuropathy

Frontiers in Neuroscience, Год журнала: 2017, Номер 11

Опубликована: Авг. 31, 2017

Chemotherapeutic agents cause many short and long term toxic side effects to peripheral nervous system that drastically alter quality of life. Chemotherapy-induced neuropathy (CIPN) is a common enduring disorder caused by several anti-neoplastic agents. CIPN typically presents with neuropathic pain, numbness distal extremities and/or oversensitivity thermal or mechanical stimuli. This adverse effect often requires reduction in chemotherapy dosage even discontinuation treatment. Currently there are no effective treatment options for CIPN. While the underlying mechanisms not understood, current data identify "dying back" axon degeneration nerve endings as major pathology this disorder. Therefore, mechanistic understanding will provide insights into pathway molecular players responsible Here, we review recent findings expand our pathogenesis discuss pathways may be shared axonal occurs during developmental pruning injury-induced Wallerian degeneration. These new avenues development therapies prevent treat

Язык: Английский

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NMNAT1 inhibits axon degeneration via blockade of SARM1-mediated NAD+ depletion

eLife, Год журнала: 2016, Номер 5

Опубликована: Окт. 13, 2016

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.

Язык: Английский

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