論文紹介著者

Daniela Yumi Kitashima（博士課程 3年）
GCOE　RA
皮膚科学教室

第一著者名・掲載雑誌・号・掲載年月

Jeannette M. Osterloh／Science 337, 481 (2012)

文献の英文表記：著者名・論文の表題・雑誌名・巻・号・ページ・発行年（西暦）

Jeannette M. Osterloh, Jing Yang, Timothy M. Rooney, A. Nicole Fox, Robert Adalbert, Eric H. Powell, Amy E. Sheehan, Michelle A. Avery, Rachel Hackett, Mary A. Logan, Jennifer M. MacDonald, Jennifer S. Ziegenfuss, Stefan Milde, Ying-Ju Hou, Carl Nathan, Aihao Ding, Robert H. Brown Jr., Laura Conforti, Michael Coleman, Marc Tessier-Lavigne, Stephan Zuchner and Marc R. Freeman. dSarm/Sarm1 Is Required for Activation of an Injury-Induced Axon Death Pathway. Science. 337 481-484, 2012

論文解説

When axons are severed in the context of peripheral neuropathy, brain injury or neurodegenerative disease, the portion of the axon distal to the injury site undergoes extensive fragmentation. The mechanism that drives this process, termed Wallerian degeneration, is not understood. Traditionally it was thought to result from passive process due to a lack of cell body-derived nutrients, however recently it has been speculated that Wallerian degeneration might be an active process that axons promote their own destruction after injury. The authors confirmed the last hypothesis and additionally identify a functional key gene of this pathway.

In experiments with flies, the authors found that a few axons remained fully intact after injury in mutant flies. From genetic study of these mutant flies, they identified a single gene affected in all: dSarm (Drosophila sterile alpha and Armadillo motif.). In other words, the reason why those mutant axons did not generate upon injury was a loss of function of dSarm, indicating that its function is necessary in neurons to drive axonal destruction after injury.

Next, they assessed Walleriam degeneration in mice that lack the correspondent in mammalians of dSarm, Sarm1. As expected in vitro experiments showed that neurons deficient in Sarm1 exhibited robust protection from degeneration compared with wild type (normal) neurons (Fig1.). Interestingly, these mutant neurons were not protected from other types of damages such as nerve growth factor deprivation, suggesting that Sarm1 protection is specific to injury-induced axon degeneration. To determine whether Sarm1 is required for Walleriam degeneration in vivo, they evaluated a sciatic nerve injury mouse model. The results showed that mice deficient of Sarm1 axons were protected from degeneration.

This research of dSarm/Sarm1 provides evidence that Walleriam degeneration is driven by an ancient, conserved axonal death program. The specific axon injury induces the activation of dSarm/Sarm1 that trigger an autodestruct program and consequently axon degeneration. Although the precise mechanism of this cascade remains unknown, this study opens doors for a new approach to the advantage of deletion of Sarm1 in animal models of neurodegenerative disease. Moreover, Sarm1 could be a promising therapeutic target in humans. Pharmacological inhibition of Sarm1 may provide benefits to patients with axonal loss and therefore may be a new treatment for peripheral neuropathy, brain injury of neurodegenerative disease