Class I and II histone deacetylase expression is not altered in human amyotrophic lateral sclerosis: Neuropathological and positron emission tomography molecular neuroimaging evidence

Abstract

Introduction There is an unmet need for mechanism‐based biomarkers and effective disease modifying treatments in amyotrophic lateral sclerosis (ALS). Previous findings have provided evidence that histone deacetylases (HDAC) are altered in ALS, providing a rationale for testing HDAC inhibitors as a therapeutic option. Methods We measured class I and II HDAC protein and transcript levels together with acetylation levels of downstream substrates by using Western blotting in postmortem tissue of ALS and controls. [11C]Martinostat, a novel HDAC positron emission tomography ligand, was also used to assess in vivo brain HDAC alterations in patients with ALS and healthy controls (HC). Results There was no significant difference in HDAC levels between patients with ALS and controls as measured by Western blotting and reverse‐transcription quantitative polymerase chain reaction. Similarly, no differences were detected in [11C]Martinostat–positron emission tomography uptake in ALS participants compared with HCs. Discussion These findings provide evidence that alterations in HDAC isoforms are not a dominant pathological feature at the bulk tissue level in ALS.

Opportunities for histone deacetylase inhibition in amyotrophic lateral sclerosis

“…In line with this, histone hypoacetylation was an associated feature in ALS models (Bennett et al, 2019; Del Signore et al, 2009; Ryu et al, 2005). However, these findings were not confirmed in an in vivo brain imaging study with a pan‐HDAC PET imaging ligand reported by Dios et al (2019). To analyse the potential of HDACs as biomarkers, the authors investigated class I and II HDAC protein and transcription levels in post‐mortem motor cortex and spinal cord samples, combining this with an in vivo [ 11 C]Martinostat (Figure 1d) study, comparing ALS patients and healthy controls.…”

“…Ample evidence links decreased histone deacetylation to neurodegeneration (Rouaux et al, 2003;Valle et al, 2014). In line with this, histone hypoacetylation was an associated feature in ALS models (Bennett et al, 2019;Del Signore et al, 2009;Ryu et al, 2005 (Dios et al, 2019). This is in contrast to earlier findings of other groups reporting HDAC differences on protein or mRNA expression levels (Janssen et al, 2010;Körner et al, 2013).…”

“…Janssen et al (2010) found HDAC2 and HDAC11 mRNA expression levels to be altered in post‐mortem brain and spinal cord tissue of ALS patients. However, a recent study by Dios et al (2019) could not find HDAC differences in post‐mortem patient tissue and in an in vivo PET imaging study. While the neurotoxic and neuroprotective roles of HDACs in neurodegenerative diseases have recently been reviewed (Thomas & D'Mello, 2018), our review highlights major findings of different HDAC subtypes, their inhibition, and their importance in (pre)clinical models of ALS.…”

“…No significant differences in HDAC levels measured by either Western blot or PCR, or in [ 11 C]Martinostat‐PET uptake were observed in ALS patients, compared to controls. It was concluded that HDAC isoform alterations may not be a dominant pathological feature at bulk tissue levels in ALS (Dios et al, 2019). This is in contrast to earlier findings of other groups reporting HDAC differences on protein or mRNA expression levels (Janssen et al, 2010; Körner et al, 2013).…”

SVA insertion in X-linked Dystonia Parkinsonism alters histone H3 acetylation associated with TAF1 gene

“…Histone extracts were obtained from XDP and control post-mortem PFC as well as XDPand control-derived fibroblasts as previously reported [54,55]. Briefly, tissues and cells were homogenized in 5% Triton buffer on ice and centrifuged at 500 g for 8 min at 4˚C to extract nuclei.…”