Activation of necroptosis in multiple sclerosis

Cell Rep. 2015 Mar 24;10(11):1836-49. doi: 10.1016/j.celrep.2015.02.051.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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