Differential effects of SARM1 inhibition in traumatic glaucoma and EAE optic neuropathies DOI Creative Commons
Pingting Liu, Wei Chen, Haowen Jiang

и другие.

Molecular Therapy — Nucleic Acids, Год журнала: 2023, Номер 32, С. 13 - 27

Опубликована: Фев. 27, 2023

Optic neuropathy is a group of optic nerve (ON) diseases with progressive degeneration ON and retinal ganglion cells (RGCs). The lack neuroprotective treatments central challenge for this leading cause irreversible blindness. SARM1 (sterile α TIR motif-containing protein 1) has intrinsic nicotinamide adenine dinucleotide (NAD+) hydrolase activity that causes axon by degrading axonal NAD+ significantly after activation injury. deletion in many, but not all, neurodegenerative disease models. Here, we compare two therapy strategies inhibition, antisense oligonucleotide (ASO) CRISPR, germline the neuroprotection three mouse This study reveals that, similar to knockout every cell, local ASO delivery adeno-associated virus (AAV)-mediated RGC-specific CRISPR knockdown provide comparable both RGC somata axons silicone oil-induced ocular hypertension (SOHU) glaucoma model only protect axons, somata, traumatic Surprisingly, neither these inhibition nor (KO) benefits or survival experimental autoimmune encephalomyelitis (EAE)/optic neuritis model. Our studies therefore suggest AAV-mediated promising gene strategy glaucomatous neuropathies demyelinating neuritis.

Язык: Английский

SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration DOI Creative Commons
Matthew D. Figley, Weixi Gu, Jeffrey D. Nanson

и другие.

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

Опубликована: Март 2, 2021

Язык: Английский

Процитировано

267
Mitophagy pathways in health and disease DOI Creative Commons
Samuel A. Killackey, Dana J. Philpott, Stephen E. Girardin

и другие.

The Journal of Cell Biology, Год журнала: 2020, Номер 219(11)

Опубликована: Авг. 14, 2020

Mitophagy is an evolutionarily conserved process involving the autophagic targeting and clearance of mitochondria destined for removal. Recent insights into complex nature overlapping pathways regulating mitophagy illustrate mitophagy's essential role in maintaining health mitochondrial network. In this review, we highlight recent studies that have changed way understood, from initiation through lysosomal degradation. We outline numerous mitophagic receptors triggers, with a focus on basal physiologically relevant cues, offering insight why they lead to also explore how maintains homeostasis at organ system levels loss may play diverse group diseases, including cardiovascular, metabolic, neurodegenerative diseases. With disrupted affecting such wide array physiological processes, deeper understanding modulate could provide avenues therapies.

Язык: Английский

Процитировано

191
The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1 DOI
Yuefeng Jiang, Tingting Liu, Chia‐Hsueh Lee

и другие.

Nature, Год журнала: 2020, Номер 588(7839), С. 658 - 663

Опубликована: Окт. 14, 2020

Язык: Английский

Процитировано

166
Small Molecule SARM1 Inhibitors Recapitulate the SARM1−/− Phenotype and Allow Recovery of a Metastable Pool of Axons Fated to Degenerate DOI Creative Commons

Robert Hughes,

Todd Bosanac,

Xianrong Mao

и другие.

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

Процитировано

143
Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy DOI Creative Commons

Todd Bosanac,

Robert Hughes,

Thomas M. Engber

и другие.

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

Процитировано

114
Shared TIR enzymatic functions regulate cell death and immunity across the tree of life DOI
Kow Essuman, Jeffrey Milbrandt, Jeffery L. Dangl

и другие.

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

Процитировано

104
Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients DOI Creative Commons
A. Joseph Bloom, Xianrong Mao, Amy Strickland

и другие.

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

Процитировано

88
SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration DOI Creative Commons
Kwang Woo Ko, Jeffrey Milbrandt, Aaron DiAntonio

и другие.

The Journal of Cell Biology, Год журнала: 2020, Номер 219(8)

Опубликована: Июль 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.

Язык: Английский

Процитировано

118
A glycolytic shift in Schwann cells supports injured axons DOI
Elisabetta Babetto, Keit Men Wong, Bogdan Beirowski

и другие.

Nature Neuroscience, Год журнала: 2020, Номер 23(10), С. 1215 - 1228

Опубликована: Авг. 17, 2020

Язык: Английский

Процитировано

116
Structural basis for SARM1 inhibition and activation under energetic stress DOI Creative Commons

Michael Sporny,

Julia Guez-Haddad,

Tami Khazma

и другие.

eLife, Год журнала: 2020, Номер 9

Опубликована: Ноя. 13, 2020

SARM1, an executor of axonal degeneration, displays NADase activity that depletes the key cellular metabolite, NAD+, in response to nerve injury. The basis SARM1 inhibition and its activation under stress conditions are still unknown. Here, we present cryo-EM maps at 2.9 2.7 Å resolutions. These indicate homo-octamer avoids premature by assuming a packed conformation, with ordered inner peripheral rings, prevents dimerization catalytic domains. This inactive conformation is stabilized binding SARM1’s own substrate NAD+ allosteric location, away from sites. model was validated mutagenesis site, which led constitutively active SARM1. We propose reduction concentration contributes disassembly SARM1's ring, allows formation domain dimers, thereby further depleting cause energetic catastrophe cell death.

Язык: Английский

Процитировано

106