Restoration of histone acetylation ameliorates disease and metabolic abnormalities in a FUS mouse model

Abstract

Dysregulation of epigenetic mechanisms is emerging as a central event in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). In many models of neurodegeneration, global histone acetylation is decreased in the affected neuronal tissues. Histone acetylation is controlled by the antagonistic actions of two protein families –the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). Drugs inhibiting HDAC activity are already used in the clinic as anti-cancer agents. The aim of this study was to explore the therapeutic potential of HDAC inhibition in the context of ALS. We discovered that transgenic mice overexpressing wild-type FUS (“Tg FUS +/+”), which recapitulate many aspects of human ALS, showed reduced global histone acetylation and alterations in metabolic gene expression, resulting in a dysregulated metabolic homeostasis. Chronic treatment of Tg FUS +/+ mice with ACY-738, a potent HDAC inhibitor that can cross the blood-brain barrier, ameliorated the motor phenotype and substantially extended the life span of the Tg FUS +/+ mice. At the molecular level, ACY-738 restored global histone acetylation and metabolic gene expression, thereby re-establishing metabolite levels in the spinal cord. Taken together, our findings link epigenetic alterations to metabolic dysregulation in ALS pathology, and highlight ACY-738 as a potential therapeutic strategy to treat this devastating disease. Electronic supplementary material The online version of this article (10.1186/s40478-019-0750-2) contains supplementary material, which is available to authorized users.

Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models

“…Statistical analysis was performed by one-way MANOVA followed by Tukey HSD post-hoc analysis: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001. (Rossaert et al 2019;Tibshirani et al 2015). The finding in the present study that arimoclomol had activity similar to RGFP109 and SAHA in preserving nuclear FUS would argue against a small indirect effect on HDAC activity being responsible.…”

“…Acetylation has multiple influences on expression of heat shock and activity of heat shock proteins, dictating the chromatin landscape for binding of HSF1 to HSE (Guertin and Lis 2010) and regulating the activity of HSF1 and HSPs (Marinova et al 2011;Marinova et al 2009;Rao et al 2012;Zelin and Freeman 2015), as well as gene expression and neuronal morphology more generally. Histone deacetylase inhibitors have neuroprotective properties on their own that are relevant to our particular interest, motor neuron disorders (Guo et al 2017;Piepers et al 2009;Rossaert et al 2019;Rouaux et al 2007;Yoo and Ko 2011), including the preservation of mutant FUS, a cause of familial ALS, in the Fig. 4 HDAC inhibitors enhanced expression of Hsp70 induced by the Hsp90 inhibitor, NXD30001.…”

Existing and Emerging Metabolomic Tools for ALS Research

“…Because PFKFB3 is known to be a positive regulator of glycolysis, this finding supports a downregulation of glucose metabolism in ALS and is consistent with the results obtained in PET and proteomic studies [23,38,39]. Moreover, we recently showed that HDAC inhibition led to the amelioration of the motor phenotype in a FUS-ALS mouse model [66]. This effect was linked to an increased expression of genes associated with glycolysis, the pentose phosphate pathway, and lipid transport, and to a decreased expression of genes related to fatty acid metabolism, partly restoring mRNA levels [66].…”

“…Moreover, we recently showed that HDAC inhibition led to the amelioration of the motor phenotype in a FUS-ALS mouse model [66]. This effect was linked to an increased expression of genes associated with glycolysis, the pentose phosphate pathway, and lipid transport, and to a decreased expression of genes related to fatty acid metabolism, partly restoring mRNA levels [66]. However, since changes at the transcriptome level do not necessarily translate into changes in the proteome or into functional changes, a fortiori not in energy metabolism, expression studies should be confirmed with functional metabolic studies [73].…”

“…For instance, histone acetylation, a regulator of chromatin folding and hence transcription factor accessibility, is highly dependent on the levels of acetyl-CoA, a product of the TCA cycle and fatty acid oxidation and the substrate for de novo fatty acid synthesis [60,61]. Moreover, histone acetyl transferases (HATs) and histone deacetylases (HDACs), the main regulators of histone acetylation, have been shown to be involved in the regulation of energy metabolism [62][63][64][65][66]. Therefore, changes in metabolic homeostasis could be closely related to changes at the epigenetic level.…”