RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS

TLDR

Mutations in the optineurin (OPTN) gene are linked to familial and sporadic ALS, yet its role in the central nervous system and contribution to disease pathology remain unclear. The study aimed to determine whether inhibiting RIPK1 kinase could protect axons in ALS and other neurodegenerative disorders. Loss of OPTN activates RIPK1/RIPK3/MLKL‑mediated necroptosis, leading to progressive axonal degeneration in mice and human ALS tissues, underscoring RIPK1/RIPK3 as key mediators and therapeutic targets.

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 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.