Abstract
SummaryActivation of the pro-degenerative protein SARM1 after diverse physical and disease-relevant injuries causes programmed axon degeneration. Original studies indicate that substantially decreased SARM1 levels are required for neuroprotection. However, we demonstrate, in Sarm1 haploinsufficient mice, that lowering SARM1 levels by 50% delays programmed axon degeneration in vivo after sciatic nerve transection and partially prevents neurite outgrowth defects in mice lacking the pro-survival factor NMNAT2. In vitro, the rate of degeneration in response to traumatic, neurotoxic, and genetic triggers of SARM1 activation is also slowed. Finally, we demonstrate that Sarm1 antisense oligonucleotides decrease SARM1 levels by more than 50% in vitro, which delays or prevents programmed axon degeneration. Combining Sarm1 haploinsufficiency with antisense oligonucleotides further decreases SARM1 levels and prolongs protection after neurotoxic injury. These data demonstrate that axon protection occurs in a Sarm1 gene dose-responsive manner and that SARM1-lowering agents have therapeutic potential, making Sarm1-targeting antisense oligonucleotides a promising therapeutic strategy.
Highlights
Sterile alpha and TIR motif containing 1 (SARM1) is a pro-degenerative NADase whose genetic removal confers strong axonal protection after injury and in preclinical disease models (Essuman et al, 2018, 2017; Geisler et al, 2019a; Gerdts et al, 2013; Henninger et al, 2016; Osterloh et al, 2012; White et al, 2019)
We found a statistically significant, partial reversal of neurite outgrowth deficits in DRG explants from Nmnat2gtE/gtE mice haploinsufficient for Sarm1 compared with those wild type for Sarm1, which are severely truncated (Figure 2E)
We found that the capacity for Sarm1 haploinsufficiency or antisense oligonucleotides (ASOs) application to delay programmed axon degeneration is transferrable from superior cervical ganglion (SCG) to DRGs in the axotomy and vincristine models (Figure S3)
Summary
Activation of the pro-degenerative protein SARM1 after diverse physical and disease-relevant injuries causes programmed axon degeneration. We demonstrate, in Sarm haploinsufficient mice, that lowering SARM1 levels by 50% delays programmed axon degeneration in vivo after sciatic nerve transection and partially prevents neurite outgrowth defects in mice lacking the pro-survival factor NMNAT2. We demonstrate that Sarm antisense oligonucleotides decrease SARM1 levels by more than 50% in vitro, which delays or prevents programmed axon degeneration. Combining Sarm haploinsufficiency with antisense oligonucleotides further decreases SARM1 levels and prolongs protection after neurotoxic injury. These data demonstrate that axon protection occurs in a Sarm gene dose-responsive manner and that SARM1-lowering agents have therapeutic potential, making Sarm1-targeting antisense oligonucleotides a promising therapeutic strategy
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