Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN

Abstract

Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a “dying-back” axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium-modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating paclitaxel-induced peripheral neuropathy (PIPN).

A Conformation-specific Nanobody Targeting the NMN-activated State of SARM1

“…Recent results show that SARM1 is not just a degradative NADase, but an auto-regulated signaling enzyme responsible for producing two calcium mobilizing messenger cADPR and NAADP 8, 23 . For example, in paclitaxel-induced peripheral neuropathy, SARM1 is activated to produce cADPR, resulting in calcium increase and AxD 17 . We and others have shown that the enzyme activities of SARM1 are specifically activated by NMN 8, 11 .…”

“…In addition to NADase activity, it also catalyzes the production of two calciummobilizing messengers, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) 8,[14][15][16] . In paclitaxel-induced peripheral neuropathy, SARM1 is activated to produce cADPR, which in turn elevates cellular calcium, resulting in AxD 17 . SARM1 is mainly expressed in neurons 18 , but can be found in variety of cells 8 .…”

Current and Emerging Pharmacotherapeutic Interventions for the Treatment of Peripheral Nerve Disorders

“…Neuronal injury or toxicity causes a reduction in NMNAT2 levels due to its rapid turnover, short half-life and the impairment of axonal transport to distal axons [ 188 ], leading to an increase in NMN:NAD + , which favours the activation of SARM1. While the impact of SARM1 on subsequent pathways is yet to be fully understood, it is thought that its activation leads to calcium influx into the axoplasm of injured axons and the breakdown of neuronal elements [ 189 , 190 , 191 ].…”

“…In SARM1-knockout mice, the development of typical neuropathic findings such as mechanical and cold hypersensitivity in oxaliplatin [ 192 ] and the loss of intraepidermal nerve fibres following paclitaxel treatment were prevented [ 193 , 194 ]. Antagonising cyclic adenosine diphosphate ribose (cADPR), a by-product of SARM1-induced axonal degeneration, with intraperitoneal injection of 8-Br-cADPR, attenuated paclitaxel-induced mechanical hypersensitivity and partially protected against the loss of intraepidermal innervation in mice, without interfering with the antitumoral effects of paclitaxel [ 191 ]. This neuroprotective impact is attributed to reduction in axonal calcium flux or inactivation of SARM1.…”

“…This neuroprotective impact is attributed to reduction in axonal calcium flux or inactivation of SARM1. Such a success has also been reflected by the protective effects demonstrated in in vitro studies involving mice and human axons exposed to paclitaxel or vincristine [ 191 , 193 , 195 ]. Small-molecule isothiazole inhibitors of SARM1 NAD-ase enzymatic activity have been demonstrated to protect against axonal morphological and functional loss in mice treated with paclitaxel [ 193 ].…”