RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

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 SOD1(G93A) transgenic mice and pathological…

• NM
  National Multiple Sclerosis Society
• NF
  Nakatomi Foundation
• HU
  Huazhong University of Science and Technology
• MM
  Mochida Memorial Foundation for Medical and Pharmaceutical Research
• DS
  Daiichi Sankyo Foundation of Life Science
• NI
  National Institutes of Health
• JS
  Japan Society for the Promotion of Science
• NI
  National Institute on Aging

  Award: 1R01AG047231
• NI
  National Institute of Allergy and Infectious Diseases

  Award: 2RO1AI075118
• NI
  National Institute of Neurological Disorders and Stroke

  Award: 1R01NS082257
• HE
  H2020 European Research Council

  Award: 323040