Acetylation state of RelA modulated by epigenetic drugs prolongs survival and induces a neuroprotective effect on ALS murine model

Scientific Reports
Lorenzo SchiaffinoRaffaella Mariotti

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, delayin...Continue Reading

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Citations

Apr 5, 2019·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration·UNKNOWN ALSUNTANGLED GROUP
Oct 28, 2019·Reviews in Endocrine & Metabolic Disorders·Estelle Grasset, Remy Burcelin
Feb 12, 2020·International Journal of Molecular Sciences·Bartłomiej BaumertBogusław Machaliński
Jul 30, 2020·British Journal of Pharmacology·Yvonne E KlinglLudo Van Den Bosch
Mar 16, 2019·Cellular & Molecular Immunology·Lei ZhangXian C Li
Nov 22, 2020·The Journal of Nutritional Biochemistry·Juan HuangFeng Jin
Apr 4, 2021·International Journal of Molecular Sciences·Youngpyo NamSang Ryong Kim

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Methods Mentioned

BETA
acetylation
co-immunoprecipitation
Assay
light microscopy

Software Mentioned

Stereoinvestigator
GraphPad Prism
PaGE
GeneSys

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