Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program

JCI Insight, Год журнала: 2019, Номер 4(17)

Опубликована: Сен. 5, 2019

Chemotherapy-induced peripheral neuropathy is one of the most prevalent dose-limiting toxicities anticancer therapy. Development effective therapies to prevent chemotherapy-induced neuropathies could be enabled by a mechanistic understanding axonal breakdown following exposure neuropathy-causing agents. Here, we reveal molecular mechanisms underlying axon degeneration induced 2 widely used chemotherapeutic agents with distinct action: vincristine and bortezomib. We showed previously that genetic deletion SARM1 blocks vincristine-induced demonstrate here it also prevents destruction administration bortezomib in vitro vivo. Using cultured neurons, found converge on core program consisting nicotinamide mononucleotide NMNAT2, SARM1, loss NAD+ but engage different upstream closely resemble Wallerian after apoptosis inhibit final common pathway preserving levels or expressing candidate gene therapeutic inhibits vitro. suggest these approaches may lead for vincristine- bortezomib-induced possibly other forms neuropathy.

Язык: Английский

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SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Proceedings of the National Academy of Sciences, Год журнала: 2016, Номер 113(41)

Опубликована: Сен. 26, 2016

Axon injury in response to trauma or disease stimulates a self-destruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner this degeneration cascade, also known as Wallerian degeneration; however, mechanism SARM1-dependent neuronal destruction still obscure. SARM1 possesses TIR domain necessary for activity. In other proteins, dimerized domains serve scaffolds innate immune signaling. contrast, dimerization consumption essential metabolite NAD+ induces destruction. This activity unique domain, yet structural elements enable are unknown. study, we identify fundamental properties promote loss degeneration. Dimerization from Caenorhabditis elegans ortholog TIR-1 leads death, indicating these activities feature function. Detailed analysis sequence homology identifies canonical motifs well SARM1-specific (SS) loop required Furthermore, residue BB dispensable injury-induced activation full-length SARM1, suggesting function requires multidomain interactions. Indeed, physical interaction between autoinhibitory N terminus revealing previously unrecognized direct connection propose mediates autoinhibition upon injury.

Язык: Английский

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Natural Killer Cells Degenerate Intact Sensory Afferents following Nerve Injury

Cell, Год журнала: 2019, Номер 176(4), С. 716 - 728.e18

Опубликована: Фев. 1, 2019

Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged preserved. We show that an endogenous ligand for natural killer (NK) receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons nerve injury, triggering selective degeneration injured axons. Infiltration cytotoxic NK cells into sciatic by extravasation occurs within 3 days crush injury. Using a combination genetic ablation and cytokine-antibody complex stimulation, we function correlates with loss sensation due afferents reduced incidence post-injury hypersensitivity. This neuro-immune mechanism cell-mediated intact sensory complements Wallerian suggests therapeutic potential modulating resolve painful neuropathy through clearance partially nerves.

Язык: Английский

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Gene therapy targeting SARM1 blocks pathological axon degeneration in mice

The Journal of Experimental Medicine, Год журнала: 2019, Номер 216(2), С. 294 - 303

Опубликована: Янв. 14, 2019

Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection models disease, suggesting that inhibiting SARM1 a promising strategy to reduce pathological AxD. Unfortunately, no drugs exist target SARM1. We, therefore, developed dominant-negatives potently block cellular axotomy neuropathy. To assess efficacy vivo, we used adeno-associated virus-mediated expression the most potent dominant-negative as model severe While axons vehicle-treated degenerate rapidly, expressing can remain intact for >10 d transection, similar protection observed mice. We thus novel vivo gene therapeutic axon approach may be applied clinically treat manifold neurodegenerative diseases characterized loss.

Язык: Английский

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

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

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