Programmed axon degeneration: from mouse to mechanism to medicine

Nature reviews. Neuroscience, Journal Year: 2020, Volume and Issue: 21(4), P. 183 - 196

Published: March 9, 2020

Language: 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, Journal Year: 2021, Volume and Issue: 34(1), P. 108588 - 108588

Published: Jan. 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.

Language: Английский

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Mechanisms of Chemotherapy-Induced Neurotoxicity

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: March 28, 2022

Since the first clinical trials conducted after World War II, chemotherapeutic drugs have been extensively used in clinic as main cancer treatment either alone or an adjuvant therapy before and surgery. Although use of improved survival patients, these are notorious for causing many severe side effects that significantly reduce efficacy anti-cancer patients' quality life. Many widely chemotherapy including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide analogs may cause direct indirect neurotoxicity. In this review we discuss on peripheral central nervous systems, neuropathic pain, chemobrain, enteric neuropathy, well nausea emesis. Understanding mechanisms involved chemotherapy-induced neurotoxicity is crucial development can protect system, symptoms experienced by millions improve outcome

Language: Английский

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

Brain, Journal Year: 2021, Volume and Issue: 144(10), P. 3226 - 3238

Published: May 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.

Language: Английский

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

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Jan. 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.

Language: Английский

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Age-related NAD+ decline

Experimental Gerontology, Journal Year: 2020, Volume and Issue: 134, P. 110888 - 110888

Published: Feb. 22, 2020

Language: Английский

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SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration

The Journal of Cell Biology, Journal Year: 2020, Volume and Issue: 219(8)

Published: July 1, 2020

Neuroinflammation and necroptosis are major contributors to neurodegenerative disease, axon dysfunction degeneration is often an initiating event. SARM1 the central executioner of pathological degeneration. Here, we demonstrate functional mechanistic links among these three pro-degenerative processes. In a neuroinflammatory model glaucoma, TNF-α induces SARM1-dependent degeneration, oligodendrocyte loss, subsequent retinal ganglion cell death. also triggers in sensory neurons via noncanonical necroptotic signaling mechanism. MLKL final canonical necroptosis; however, axonal necroptosis, does not directly trigger Instead, loss survival factors NMNAT2 STMN2 activate NADase activity, which leads calcium influx Hence, findings define specialized form necroptosis. The demonstration that signals can act locally stimulate identifies therapeutically targetable mechanism by neuroinflammation disease.

Language: Английский

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The SARM1 axon degeneration pathway: control of the NAD+ metabolome regulates axon survival in health and disease

Current Opinion in Neurobiology, Journal Year: 2020, Volume and Issue: 63, P. 59 - 66

Published: April 17, 2020

Language: Английский

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Axons Matter: The Promise of Treating Neurodegenerative Disorders by Targeting SARM1-Mediated Axonal Degeneration

Trends in Pharmacological Sciences, Journal Year: 2020, Volume and Issue: 41(4), P. 281 - 293

Published: Feb. 24, 2020

Attempts to develop neuroprotective treatments for neurodegenerative disorders have not yet been clinically successful. Axonal degeneration has recognized as a predominant driver of disability and disease progression in central nervous system (CNS) diseases such amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease, peripheral (PNS) chemotherapy-induced, diabetic, inherited neuropathies, ocular disorders, glaucoma. In recent years, sterile alpha TIR motif containing 1 (SARM1) emerged the first compelling axonal-specific target therapeutic intervention. this review, we discuss role axonal with focus on SARM1 discovery its intrinsic enzymatic function. Establishment neurofilament light chain (NfL) reliable biomarker damage, availability an ultrasensitive method measuring NfL plasma or serum, provide translational tools make development protective, inhibitors viable approach treat disorders.

Language: Английский

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cADPR is a gene dosage-sensitive biomarker of SARM1 activity in healthy, compromised, and degenerating axons

Experimental Neurology, Journal Year: 2020, Volume and Issue: 329, P. 113252 - 113252

Published: Feb. 19, 2020

Language: Английский

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