Mutations in 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 is unclear. Here, we found that optineurin actively suppressed RIPK1-dependent signaling by regulating its turnover. Loss-of-OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery, including RIPK1, RIPK3 and MLKL, in the CNS. Furthermore, RIPK1/RIPK3-mediated axonal pathology was commonly observed in SOD1G93A transgenic mice and pathological samples from human ALS. Thus, RIPK1/RIPK3 plays a critical role in mediating progressive axonal degeneration and inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration.

Apoptosis is crucial for the normal development of the nervous system, whereas neurons in the adult CNS are relatively resistant to this form of cell death. However, under pathological conditions, upregulation of death receptor family ligands, such as tumour necrosis factor (TNF), can sensitize cells in the CNS to apoptosis and a form of regulated necrotic cell death known as necroptosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). Necroptosis promotes cell death and neuroinflammation to mediate pathogenesis in several neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease and Alzheimer disease. In this Review, we outline the evidence implicating necroptosis in these neurological diseases, and suggest that targeting RIPK1 might help to inhibit multiple cell death pathways and ameliorate neuroinflammation.

Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. TNFα, a proinflammatory cytokine implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8 deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as, activation of RIPK1, RIPK3 and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as AD, PD and HD. Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNFα, and inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS and suggest that targeting RIPK1 may represent a novel therapeutic strategy for MS.

Receptor-interacting protein 1 (RIP1) kinase has emerged as a key upstream regulator that controls inflammatory signalling as well as the activation of multiple cell death pathways, including apoptosis and necroptosis. The ability of RIP1 to modulate these key cellular events is tightly controlled by ubiquitylation, deubiquitylation and the interaction of RIP1 with a class of ubiquitin receptors. The modification of RIP1 may thus provide a unique 'ubiquitin code' that determines whether a cell activates nuclear factor-κB (NF-κB) to promote inflammatory signalling or induces cell death by apoptosis or necroptosis. Targeting RIP1 might be a novel therapeutic strategy for the treatment of both acute and chronic human diseases.