. Neurobiology. SARM1 activation triggers axon degeneration locally via NAD⁺ destruction. Science. 2015 Apr 24;348(6233):453-7. Epub 2015 Apr 23 PubMed.


Please login to recommend the paper.


  1. Progress in science usually comes from considering two apparently contradictory findings and asking how both can be correct. On this occasion there are two such results. One is the striking data reported by Gerdts and colleagues indicating that artificial dimerization of the SARM1 TIR domain (sTIR) can deplete NAD and induce axon degeneration and cell death. The other data, which were already published by at least three groups, indicated that a drug that depletes NAD, FK866, phenocopies WLDS expression: It preserves axons in several contexts, including injured neurites in primary culture, explanted nerve-muscle preparations, and severed axons in zebrafish embryos (Sasaki et al., 2009; Di Stefano et al., 2014; Shen et al., 2014). Gerdts et al. cite one of these papers from their own group (Sasaki et al., 2009) in a manner unrelated to neuroprotection, while not citing the others. Consequently, what we consider to be the most interesting implications of these data are not discussed.

    It is puzzling how SARM1-mediated depletion of NAD relates to the rapid loss of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and to alterations in NAD and other related metabolites in injured axons/nerves. NMNAT2 appears to be the major NMNAT isoform in axons and is essential for their survival (Gilley and Coleman, 2010). Because NMNAT2 has a short half-life, and since NAD is constantly turned over, loss of the enzyme in injured axons could itself be sufficient to underlie the decline in NAD. Crucially, a rise in the NMNAT substrate, NMN, which seems to be pro-degenerative, is also seen in injured nerves while the NMNAT product, NAD, falls (Di Stefano et al., 2014). This rise in NMN fits less easily with SARM1-mediated NAD depletion being the sole driver of axon degeneration. NMN would only accumulate if the enzyme needed to take it away (NMNAT, and probably specifically NMNAT2) was missing. In fact, NAD levels decline substantially in the absence of SARM1 within five days of nerve injury, though the axons continue to survive for over two weeks (Gilley et al., 2015). Interestingly, mice lacking NMNAT2 die at birth due to an extensive axon defect (Gilley et al., 2013), and we have recently shown that SARM1 depletion totally rescues this phenotype, allowing mice to survive and remain healthy up to at least 12 months of age. However, SARM1 depletion seems to work in these mice via a mechanism that appears largely independent of changes to NAD (or NMN) levels (Gilley et al., 2015). Hence, Gerdts et al.'s finding that NAD levels are partially maintained in the absence of SARM1 30h after a nerve lesion does not easily explain the survival of NMNAT2 null mice for up to 12 months when SARM1 is also removed. This, too, suggests there is more to the story.

    What the field now needs is a balanced review (or several reviews from different authors) on this topic that attempts to reconcile these different findings. The history of this field shows that this is how progress is made. The 2004 publication of axon preservation by heavily overexpressed NMNAT1 in primary culture (Araki et al., 2004), followed by findings that NMNAT1 does not preserve axons in transgenic mice (Conforti et al., 2007; Yahata et al., 2009), were key factors leading to the identification of NMNAT2 as an endogenous axon survival factor (Gilley and Coleman, 2010). This led us to propose an attractive and simple model in which the aberrant WLDS fusion protein, or mislocalized NMNAT1 (due to high overexpression or mutation), deliver stable NMNAT1 activity into axons (where it is not normally found) to functionally substitute for loss of labile NMNAT2. It will be fascinating to see how the apparent contradictions raised by this new study resolve themselves this time.

    Alzheimer’s disease involves massive loss of synapses and white matter and readers of this forum will be aware that it is important in the longer term to know whether the Wallerian axon degeneration pathway is at least partially responsible for this. This is a more complex question, but progress toward understanding the NMNAT/SARM1 pathway is an essential first step. Eventually the aim will be to ask whether markers and modifiers of this pathway play key roles in animal models, and ultimately human cases, of Alzheimer’s disease. 


    . Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 2004 Aug 13;305(5686):1010-3. PubMed.

    . NAD(+) and axon degeneration revisited: Nmnat1 cannot substitute for Wld(S) to delay Wallerian degeneration. Cell Death Differ. 2007 Jan;14(1):116-27. PubMed.

    . A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration. Cell Death Differ. 2015 Apr;22(5):731-42. Epub 2014 Oct 17 PubMed.

    . Rescue of peripheral and CNS axon defects in mice lacking NMNAT2. J Neurosci. 2013 Aug 14;33(33):13410-24. PubMed.

    . Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLoS Biol. 2010 Jan 26;8(1):e1000300. PubMed.

    . Absence of SARM1 Rescues Development and Survival of NMNAT2-Deficient Axons. Cell Rep. 2015 Mar 31;10(12):1974-81. Epub 2015 Mar 26 PubMed.

    . Nicotinamide mononucleotide adenylyl transferase-mediated axonal protection requires enzymatic activity but not increased levels of neuronal nicotinamide adenine dinucleotide. J Neurosci. 2009 Apr 29;29(17):5525-35. PubMed.

    . Transgenic mice expressing the Nmnat1 protein manifest robust delay in axonal degeneration in vivo. J Neurosci. 2009 May 20;29(20):6526-34. PubMed.

    . Maintaining energy homeostasis is an essential component of Wld(S)-mediated axon protection. Neurobiol Dis. 2013 Nov;59:69-79. Epub 2013 Jul 24 PubMed.

    . Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration. J Neurosci. 2009 May 13;29(19):6276-84. PubMed.

Make a Comment

To make a comment you must login or register.

This paper appears in the following:


  1. An Axon Self-Destruct Button Triggers Energy Woes