Activation of necroptosis in multiple sclerosis

Dimitry Ofengeim, Yasushi Ito, Ayaz Najafov, Yaoyang Zhang, Bing Shan, Judy Park DeWitt, Juanying Ye, Xumin Zhang, Ansi Chang, Helin Vakifahmetoglu-Norberg, Jiefei Geng, Benedicte Py, Wen Zhou, Palak Amin, Jonilson Berlink Lima, Chunting Qi, Qiang Yu, Bruce Trapp, Junying Yuan

Research output: Contribution to journalArticlepeer-review

286 Scopus citations

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 andsuggest that targeting RIPK1 may represent a therapeutic strategy for MS.

Original languageEnglish (US)
Pages (from-to)1836-1849
Number of pages14
JournalCell Reports
Volume10
Issue number11
DOIs
StatePublished - Mar 24 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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