A new SARM1s race in ALS begins

Energy drain. SARM1 is an NAD+ase, triggering axonal destruction by locally depleting ATP (see February 2015, April 2015 news; Gerdts et al., 2015; Yang et al., 2015). [Image: Essuman et al., 2017, Neuron.]

The axon executioner SARM1 is an enzyme and therefore potentially druggable according to a new study. The study, led by Washington University St Louis’ Jeffrey Milbrandt in Missouri, found that SARM1 catalyzed the cleavage of NAD+, a key cofactor needed for ATP synthesis (Essuman et al., 2017). Milbrandt’s team previously demonstrated that SARM1 triggered axon degeneration by depleting its energy by reducing the availability of NAD+ (see April 2015 news; Gerdts et al., 2015).

The findings build on studies in 2012 led by Marc Freeman at the University of Massachusetts Medical School in Worcester which found that injured axons self destruct through a SARM1-mediated mechanism (see June 2012 news; Osterloh et al., 2012).

The study is published on March 16 in Neuron.

Researchers discovered in 2014 that SARM1 may play a role to ALS by performing genome-wide association studies (GWAS) of sporadic disease. The study, led by Istituto Auxologico Italiano’s Vincenzo Silani in Italy, found that variants in the SARM1 gene significantly associated with the disease (P = 1.11 × 10(-8); OR 0.82) (Fogh et al., 2014). Subsequent GWAS analysis led by King’s College London’s Ammar Al-Chalabi in England, UMC Utrecht’s Jan Veldink and Leonard van den Berg in the Netherlands confirmed these conclusions (van Rheenan et al. 2016).

Meanwhile, J. Alex Parker’s team at the University of Montreal Hospital Research Center in Canada turned to C. elegans to determine whether SARM1 may contribute to axonal loss in ALS, which may occur before the first signs of the disease (see Fischer and Glass, 2007). The study, published in 2015, found that SARM1 mediated the degeneration of motor neurons in a TDP-43 and a FUS model of ALS (see June 2015 news; Vérièpe et al., 2015).

The findings add to previous observations from the University of Massachusetts Medical School’s Robert Brown and Marc Freeman presented at the 2013 Drosophila Research Conference in Washington, D.C, which indicated that SARM1 may contribute to the destruction of at least 50% of motor neurons in a SOD1 model of the disease (see April 2013 news).

Together, the results suggest that sARM1 may contribute to ALS and therefore may be a potential target in the disease.

Featured Paper

Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. The SARM1 Toll/Interleukin-1 Receptor Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. 2017 Mar 22;93(6):1334-1343.e5. [PubMed] .

References

Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J. SARM1 activation triggers axon degeneration locally via NAD⁺ destruction. Science. 2015 Apr 24;348(6233):453-7. [PubMed].

Yang J, Wu Z, Renier N, Simon DJ, Uryu K, Park DS, Greer PA, Tournier C, Davis RJ, Tessier-Lavigne M. Pathological axonal death through a MAPK cascade that triggers a local energy deficit. Cell. 2015 Jan 15;160(1-2):161-76. [PubMed].

Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA, Hackett R, Logan MA, MacDonald JM, Ziegenfuss JS, Milde S, Hou YJ, Nathan C, Ding A, Brown RH Jr, Conforti L, Coleman M, Tessier-Lavigne M, Züchner S, Freeman MR. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science. 2012 Jul 27;337(6093):481-4. [PubMed].

Vérièpe J, Fossouo L, Parker JA. Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons. Nat Commun. 2015 Jun 10;6:7319. [PubMed].

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Image on the home page: SARM1-mediated degeneration of mouse axons. Josiah Gerdts, while in the Milbrandt lab. Courtesy of Washington University St-Louis.

axon degeneration disease-als sarm1 topic-preclinical
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