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

Abstract

Axons are essential for nervous system function and axonal pathology is a common hallmark of many neurodegenerative diseases. Over a century and a half after the original description of Wallerian axon degeneration, advances over the past five years have heralded the emergence of a comprehensive, mechanistic model of an endogenous axon degenerative process that can be activated by both injury and disease. Axonal integrity is maintained by the opposing actions of the survival factors NMNAT2 and STMN2 and pro-degenerative molecules DLK and SARM1. The balance between axon survival and self-destruction is intimately tied to axonal NAD⁺ metabolism. These mechanistic insights may enable axon-protective therapies for a variety of human neurodegenerative diseases including peripheral neuropathy, traumatic brain injury and potentially ALS and Parkinson's.

Fig. 1.

A schematic describing the endogenous Wallerian degeneration pathway.

Fig. 2.

A. SARM1 contains an auto-inhibitory N-terminus, two tandem SAM domains and a C-terminal TIR domain. B. The crystal structure of SARM1’s SAM domains, which form an octomer (Image of PDB ID:6QWV[26], created with EzMol[76]). The side-view shows that the tandem SAM domains form two stacking rings in the octomer. C. A schematic of SARM1 at rest, where the N-terminus interacts with the TIR, preventing its dimerization, and after injury-induced activation, where the N-terminus-TIR interaction is disrupted and the TIR’s multimerize, leading to enzymatic degradation of NAD⁺. D. SARM1 cleaves NAD⁺ into Nam and ADPR, and can also cyclize ADPR into cyclic ADPR.

Fig. 3.

The NAD⁺ metabolic pathway. In the axon, NMN is turned into NAD⁺ by NMNAT2. When activated, SARM1 degrades NAD⁺ into nicotinamide (Nam) and ADPR or cyclic ADPR (cADPR). NMN may activate SARM1 (indicated by dashed line). Nam can be converted back to NMN by NAMPT. Another source of NMN is NR phosphorylated by NRK. The bacterial enzyme NMN deamidase can convert NMN to its deamidated counterpart, nicotinic acid mononucleotide (NaMN). Nicotinic acid riboside (NaR) and nicotinic acid (Na) can be alternate sources of NaMN (via NRK or NAPRT, respectively). NaMN can be also be made into NAD⁺ via conversion to NaAD by NMNAT2 and then by NADsyn into NAD⁺.