title: Activation of necroptosis in multiple sclerosis.
abstract: Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. Tumor necrosis factor α (TNF-α), 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 Alzheimer's disease (AD), Parkinson’s disease (PD), and Huntington's disease (HD). Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNF-α and that 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 therapeutic strategy for MS.
authors: Dimitry
authors: D
authors: Ofengeim
authors: Yasushi
authors: Y
authors: Ito
authors: Ayaz
authors: A
authors: Najafov
authors: Yaoyang
authors: Y
authors: Zhang
authors: Bing
authors: B
authors: Shan
authors: Judy Park
authors: JP
authors: DeWitt
authors: Juanying
authors: J
authors: Ye
authors: Xumin
authors: X
authors: Zhang
authors: Ansi
authors: A
authors: Chang
authors: Helin
authors: H
authors: Vakifahmetoglu-Norberg
authors: Jiefei
authors: J
authors: Geng
authors: Benedicte
authors: B
authors: Py
authors: Wen
authors: W
authors: Zhou
authors: Palak
authors: P
authors: Amin
authors: Jonilson
authors: J
authors: Berlink Lima
authors: Chunting
authors: C
authors: Qi
authors: Qiang
authors: Q
authors: Yu
authors: Bruce
authors: B
authors: Trapp
authors: Junying
authors: J
authors: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
chemical_list: D020543:Proteome; D014409:Tumor Necrosis Factor-alpha; C570693:MLKL protein, human; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053181:Caspase 8