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Sarm1 haploinsufficiency or low expression levels after antisense oligonucleotides delay programmed axon degeneration

Published version
Peer-reviewed

Type

Article

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Authors

Gould, Stacey Anne 
Gilley, Jonathan 
Ling, Karen 
Jafar-Nejad, Paymaan 
Rigo, Frank 

Abstract

Activation 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.

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Journal Title

CELL REPORTS

Conference Name

Journal ISSN

2211-1247
1556-5068

Volume Title

Publisher

Elsevier
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/K012983/2)