Distribution of histone deacetylases in post-mortem brain and spinal cord of ALS patients and controls

Transcriptional dysregulation has been shown both in human sporadic ALS and in the G93A mouse model (Olsen et al., 2001; Malaspina and de Belleroche, 2004; Ishigaki et al., 2002; Yoshihara et al., 2002). Histone deacetylases (HDAC) catalyze the deacetylation of lysine residues in the amino terminals of the highly conserved core histones H2A, H2B, H3, and H4. The posttranscriptional acetylation of lysine residues in the amino terminals of the core histones leads to a neutralization of the positive charge, and opening of the DNA conformation which allows access of transcription factors to target genes. Therefore, acetylation of histones correlates with transcriptional activity and determines specific temporal and spatial gene expression patterns (Pogo et al., 1966; Grunstein, 1997). HDAC enzymes have become potential therapeutic targets for several diseases, among them malignant, cardiovascular and neurodegenerative disorders. In the G93A-ALS-mouse model, HDAC inhibitors have already been shown to have neuroprotective capacities (Ryu et al., 2005; Petri et al., 2006). HDAC can be grouped into four classes, class I (HDAC 1–3, 8), class II (HDAC 4–7, 9, 10), class II (syn. SIRT 1–7) and class IV (HDAC 11) with distinct localization, substrates and physiological roles. The mRNA expression levels of HDAC 1–11 have previously been characterized in rat brain ((Broide et al., 2006) but not yet studied in human tissue.