RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

Yasushi Ito, Dimitry Ofengeim, Ayaz Najafov, Sudeshna Das, Shahram Saberi, Ying Li, Junichi Hitomi, Hong Zhu, Hongbo Chen, Lior Mayo, Jiefei Geng, Palak Amin, Judy Park DeWitt, Adnan Kasim Mookhtiar, Marcus Florez, Amanda Tomie Ouchida, Jian Bing Fan, Manolis Pasparakis, Michelle A. Kelliher, John RavitsJunying Yuan

Research output: Contribution to journalArticlepeer-review

297 Scopus citations

Abstract

Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor-interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1G93A transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.

Original languageEnglish (US)
Pages (from-to)603-608
Number of pages6
JournalScience
Volume353
Issue number6299
DOIs
StatePublished - Aug 5 2016
Externally publishedYes

ASJC Scopus subject areas

  • General

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