RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS
Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology | Nervous System Diseases | Neuroscience and Neurobiology
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 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.
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Citation: Science. 2016 Aug 5;353(6299):603-8. doi: 10.1126/science.aaf6803. Link to article on publisher's site
Ito, Yasushi; Kelliher, Michelle A.; and Yuan, Junying, "RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS" (2016). UMass Metabolic Network Publications. 33.