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 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
• Journal: Cell reports (Cell Rep) Vol. 10 Issue 11 Pg. 1836-49 (Mar 24 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 25801023 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Proteome
• Tumor Necrosis Factor-alpha
• MLKL protein, human
• Protein Kinases
• Receptor-Interacting Protein Serine-Threonine Kinases
• Caspase 8

Topics

• Animals
• Apoptosis
• Caspase 8 (metabolism)
• Cerebral Cortex (metabolism, pathology)
• Humans
• Mice
• Mice, Inbred C57BL
• Multiple Sclerosis (metabolism, pathology)
• Necrosis
• Oligodendroglia (drug effects, metabolism)
• Protein Kinases (genetics)
• Proteome (genetics, metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (genetics, metabolism)
• Spinal Cord (metabolism, pathology)
• Tumor Necrosis Factor-alpha (toxicity)