Acetylation State of RelA Modulated by Epigenetic Drugs Prolongs Survival and Induces a Neuroprotective Effect on ALS Murine Model

Sci Rep. 2018 Aug 27;8(1):12875. doi: 10.1038/s41598-018-30659-4.

Abstract

Dysregulation in acetylation homeostasis has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. It is known that the acetylation of transcriptional factors regulates their activity. The acetylation state of NF-kB RelA has been found to dictate the neuroprotective versus the neurotoxic effect of p50/RelA. Here we showed that the pro-apoptotic acetylation mode of RelA, involving a general lysine deacetylation of the subunit with the exclusion of the lysine 310, is evident in the lumbar spinal cord of SOD1(G93A) mice, a murine model of ALS. The administration of the HDAC inhibitor MS-275 and the AMPK/sirtuin 1 activator resveratrol restored the normal RelA acetylation in SOD1(G93A) mice. The SOD1(G93A) mice displayed a 3 weeks delay of the disease onset, associated with improvement of motor performance, and 2 weeks increase of lifespan. The epigenetic treatment rescued the lumbar motor neurons affected in SOD1(G93A) mice, accompanied by increased levels of protein products of NF-kB-target genes, Bcl-xL and brain-derived neurotrophic factor. In conclusion, we here demonstrate that MS-275 and resveratrol restore the acetylation state of RelA in the spinal cord, delaying the onset and increasing the lifespan of SOD1(G93A) mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amyotrophic Lateral Sclerosis / drug therapy
  • Amyotrophic Lateral Sclerosis / etiology
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / mortality*
  • Animals
  • Biomarkers
  • Disease Models, Animal
  • Epigenesis, Genetic / drug effects*
  • Histones / metabolism
  • Mice
  • Motor Neurons / metabolism
  • Neurodegenerative Diseases / etiology
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Neuroprotective Agents / pharmacology*
  • Prognosis
  • Resveratrol / pharmacology
  • Signal Transduction
  • Spinal Cord / metabolism
  • Superoxide Dismutase / metabolism
  • Transcription Factor RelA / metabolism*
  • Treatment Outcome

Substances

  • Biomarkers
  • Histones
  • Neuroprotective Agents
  • Transcription Factor RelA
  • Superoxide Dismutase
  • Resveratrol