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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

438 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
Pages (from-to)603-608
Number of pages6
JournalScience
Volume353
Issue number6299
DOIs
StatePublished - 5 Aug 2016
Externally publishedYes

Funding

FundersFunder number
Harvard Institute of Medicine
NeuroBehavior Laboratory
National Institutes of Health
National Institute on Aging1R01AG047231
National Institute on Aging
National Institute of Allergy and Infectious DiseasesR01AI075118
National Institute of Allergy and Infectious Diseases
National Institute of Neurological Disorders and Stroke1R01NS082257
National Institute of Neurological Disorders and Stroke
National Multiple Sclerosis Society
Harvard University7-Cl-O-Nec-1
Harvard University
Nakatomi Foundation
European Research Council323040
European Research Council
Japan Society for the Promotion of Science
National Natural Science Foundation of China31530041
National Natural Science Foundation of China
Huazhong University of Science and TechnologyRipk3-/-
Huazhong University of Science and Technology
Mochida Memorial Foundation for Medical and Pharmaceutical Research
Daiichi Sankyo Foundation of Life Science
Universität zu Köln
National Major Science and Technology Projects of China2014ZX09102001-002
National Major Science and Technology Projects of China

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