SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration

Neuron, Год журнала: 2021, Номер 109(7), С. 1118 - 1136.e11

Опубликована: Март 2, 2021

Язык: Английский

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Small Molecule SARM1 Inhibitors Recapitulate the SARM1−/− Phenotype and Allow Recovery of a Metastable Pool of Axons Fated to Degenerate

Cell Reports, Год журнала: 2021, Номер 34(1), С. 108588 - 108588

Опубликована: Янв. 1, 2021

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 SARM1 recapitulates SARM1-/- phenotype protects from induced by axotomy or mitochondrial dysfunction. inhibition post-mitochondrial injury with rotenone allows recovery rescues already entered state. conclude molecules has potential treat axonopathies peripheral nervous systems preventing allowing functional damaged, viable, axons.

Язык: Английский

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Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy

Brain, Год журнала: 2021, Номер 144(10), С. 3226 - 3238

Опубликована: Май 6, 2021

Abstract Axonal degeneration is an early and ongoing event that causes disability disease progression in many neurodegenerative disorders of the peripheral central nervous systems. Chemotherapy-induced neuropathy (CIPN) a major cause morbidity main dose reductions discontinuations cancer treatment. Preclinical evidence indicates activation Wallerian-like pathway driven by sterile alpha TIR motif containing 1 (SARM1) responsible for axonopathy CIPN. SARM1 driver evolutionarily conserved programme axonal downstream chemical, inflammatory, mechanical or metabolic insults to axon. contains intrinsic NADase enzymatic activity essential its pro-degenerative functions, making it compelling therapeutic target treat neurodegeneration characterized axonopathies Small molecule inhibitors have potential prevent provide transformational disease-modifying treatment these disorders. Using biochemical assay we identified novel series potent selective irreversible isothiazole protected rodent human axons vitro. In sciatic nerve axotomy, observed decreased rise cADPR plasma neurofilament light chain released from injured nerves vivo. mouse paclitaxel model CIPN determined Sarm1 knockout mice prevented loss function, assessed sensory action amplitudes tail nerve, gene-dosage-dependent manner. model, intraepidermal fibres induced provided partial protection function amplitude allodynia.

Язык: Английский

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Shared TIR enzymatic functions regulate cell death and immunity across the tree of life

Science, Год журнала: 2022, Номер 377(6605)

Опубликована: Июль 7, 2022

In the 20th century, researchers studying animal and plant signaling pathways discovered a protein domain that is shared across diverse innate immune systems: Toll/interleukin-1/resistance gene (TIR) domain. The TIR found in several architectures was defined as an adaptor mediates protein-protein interactions immunity developmental pathways. However, studies of nerve degeneration animals-and subsequent breakthroughs plant, bacterial, archaeal systems-revealed domains possess enzymatic activities. We provide synthesis functions role various related products evolutionarily systems. These may ultimately guide interventions would span tree life, from treating human neurodegenerative disorders bacterial infections to preventing diseases.

Язык: Английский

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Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules

Molecular Cell, Год журнала: 2022, Номер 82(9), С. 1643 - 1659.e10

Опубликована: Март 25, 2022

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

Язык: Английский

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Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients

Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)

Опубликована: Янв. 6, 2022

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 enzymatic activity all 42 rare alleles identified among 8507 amyotrophic lateral sclerosis (ALS) patients 9671 controls. We then intrathecally injected mice with virus expressing constructs test capacity an ALS-associated variant neurodegeneration vivo. Results Twelve out missense or small in-frame deletions exhibit constitutive NADase activity, including more than half those are unique ALS occur multiple patients. There > 5-fold enrichment compared Expression dorsal root ganglion (DRG) pro-degenerative cytotoxic. Intrathecal injection AAV common reference allele innocuous mice, construct harboring V184G , found most frequently patients, causes loss, motor dysfunction, sustained neuroinflammation. Conclusions These results implicate hypermorphic as candidate genetic factors other conditions.

Язык: Английский

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Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering

Molecular Aspects of Medicine, Год журнала: 2023, Номер 92, С. 101193 - 101193

Опубликована: Июнь 16, 2023

Glaucoma is a common, complex, multifactorial neurodegenerative disease characterized by progressive dysfunction and then loss of retinal ganglion cells, the output neurons retina. most common cause irreversible blindness affects ∼80 million people worldwide with many more undiagnosed. The major risk factors for glaucoma are genetics, age, elevated intraocular pressure. Current strategies only target pressure management do not directly processes occurring at level cell. Despite to manage pressure, as 40% patients progress in least one eye during their lifetime. As such, neuroprotective that cell these great therapeutic need. This review will cover recent advances from basic biology on-going clinical trials neuroprotection covering degenerative mechanisms, metabolism, insulin signaling, mTOR, axon transport, apoptosis, autophagy, neuroinflammation. With an increased understanding both mechanisms disease, we closer than ever strategy glaucoma.

Язык: Английский

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Axonal energy metabolism, and the effects in aging and neurodegenerative diseases

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Июль 20, 2023

Abstract Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of (NDAs), such as Alzheimer’s disease, Parkinson’s Huntington’s Amyotrophic lateral sclerosis. Glucose is the major brain fuel glucose hypometabolism has been observed regions vulnerable to NDAs. Many susceptible are topological central hub connectome, linked by densely interconnected long-range axons. Axons, key components have high metabolic needs support neurotransmission other essential activities. Long-range axons particularly injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy often an early sign neurodegeneration. Recent ascribe axonal maintenance failures local dysregulation. With this review, we aim stimulate research exploring metabolically oriented neuroprotection strategies enhance or normalize bioenergetics NDA models. Here start summarizing evidence from human patients animal models reveal correlation between connectomic disintegration aging/NDAs. To encourage mechanistic investigations on how dysregulation occurs during aging/NDAs, first review current literature distinct subdomains: axon initial segments, myelinated arbors harboring pre-synaptic boutons. In each subdomain, focus organization, activity-dependent regulation system, external glial support. Second, mechanisms regulating nicotinamide adenine dinucleotide (NAD + ) homeostasis, molecule for energy metabolism processes, including NAD biosynthetic, recycling, consuming pathways. Third, highlight innate vulnerability connectome discuss its perturbation As deficits developing into NDAs, especially asymptomatic phase, they likely exaggerated further impaired energetic cost neural network hyperactivity, pathology. Future interrogating causal relationship vulnerability, axonopathy, amyloid/tau pathology, cognitive decline will provide fundamental knowledge therapeutic interventions.

Язык: Английский

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Activation of retinal glial cells contributes to the degeneration of ganglion cells in experimental glaucoma

Progress in Retinal and Eye Research, Год журнала: 2023, Номер 93, С. 101169 - 101169

Опубликована: Фев. 1, 2023

Язык: Английский

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Regulated cell death and its role in Alzheimer’s disease and amyotrophic lateral sclerosis

Acta Neuropathologica, Год журнала: 2024, Номер 147(1)

Опубликована: Апрель 7, 2024

Язык: Английский

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