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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects upper and lower motor neurons (MNs)
In order to evaluate the effect of MS-275 and resveratrol in Superoxide Dismutase 1 gene (SOD1)(G93A) mice, behavioral tests were performed in all groups of animals: control group (VEH n = 10), Low Doses group (68 μg/Kg of resveratrol and 2 μg/Kg of MS-275; LD n = 14) and High Doses group (136 μg/Kg of resveratrol and 4 μg/Kg of MS-275; HD n = 10)
Song and colleagues found that the administration of resveratrol (25 mg/kg/day) increased the lifespan of SOD1(G93A) mice of 11% compared to controls
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects upper and lower motor neurons (MNs). It has been reported that RelA subunit is increased in mutant SOD1 MNs in in vitro model of ALS and in spinal MNs of ALS patients[14,15], supporting a direct correlation between RelA activation and MNs degenerations Those studies did not focus the RelA acetylation state in MNs, they reported that the MNs vulnerability to the mutated SOD1 astrocyte-conditioned medium was dependent on the activation of the phosphorylated form of RelA, known to enhance RelA acetylation at the K310 residue[16]. Our results demonstrate that the combined administration of these epigenetic drugs, tested at two different doses, both in the micrograms range, reestablished the proper acetylation state of RelA in the lumbar spinal cord of SOD1(G93A) mice Most relevant, it provided a neuroprotective effect by causing a delay of the disease onset with an improvement of the motor performance and, an elongation of animal survival
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