Augustus Waller's foresight realized: SARM1 in peripheral neuropathies

Abstract

Peripheral neuropathy is a common neurodegenerative condition characterized by numbness, tingling, pain, and weakness that frequently starts in the distal limbs. Arising from multiple etiologies, many peripheral neuropathies exhibit a slowly progressive course due to axon degeneration for which no effective treatments exist. During the past decade, numerous crucial insights into mechanisms of axon degeneration in peripheral neuropathies emerged from experiments involving nerve-cutting procedures, revealing the central role of the SARM1 axon degeneration pathway in both. Here I review commonalities and differences in the role of SARM1 after nerve cut and in several acquired and inherited peripheral neuropathies. This new knowledge now paves the way for the development of therapeutics that directly address root causes of various kinds of neuropathies.

Figure 1:

Schematic depicting SARM1-mediated axon degeneration in peripheral neuropathies. Chemotherapeutics activate the SARM1 pathway by either directly decreasing NMNAT2 or inducing mitochondrial dysfunction and reactive oxygen species production (ROS), which leads to a decrease of NMNAT2 and SARM1 activation. Mutations in NMNAT2 or in mitochondrial proteins as observed in some inherited neuropathies lead to decreased NMNAT2 function or mitochondrial dysfunction. Decreased NMNAT2 leads to an increase in NMN and decrease of NAD⁺, thereby activating SARM1, which cleaves NAD⁺, resulting in increased ADPR or cADPR, decrease of ATP and axon degeneration. Certain neurotoxins can activate SARM1 directly by binding to the NMN site. Therapeutic opportunities to block SARM1-mediated axon degeneration are shown in maroon font. DLK inhibitors and Stat1/3 activators increase NMNAT2 levels, thereby increasing axonal NAD⁺ and inhibiting SARM1. Oral nicotinamide riboside and nicotinamide mononucleotide are metabolized into NAD⁺ thereby countering SARM1-mediated NAD⁺ loss and directly inhibiting SARM1. SARM1 inhibitors and SARM1-dominant/negatives block SARM1 activation, whereas SARM1 antisense-oligonucleotides decrease the amount of SARM1 available. cADPR blockers prevent calcium influx. Green ovals: etiologies for acquired neuropathies, yellow ovals: etiologies for hereditary neuropathies. Red arrows: activating; blue lines: inhibiting/decreasing; Abbreviations: ADPR - adenosine diphosphate ribose; ATP - adenosine triphosphate; cADPR - cyclic ADPR; NAD⁺ - nicotinamide dinucleotide; Nam – nicotinamide; NMN - nicotinamide mononucleotide; NMNAT2 - nicotinamide nucleotide adenylyltransferase 2; SARM1 - sterile alpha and TIR motif containing 1.