DMMC Course: EPIGENETICS: FROM MECHANISMS TO MEDICINES

1610-1700 Tuesday 26 June 2007. O’Reilly Hall, University College Dublin.

Therapeutic Potential of Targeting the Epigenome in Neurodegenerative Conditions
Hoon Ryu and Robert J. Ferrante (Boston University School of Medicine)

Chromatin remodeling and transcription regulation are tightly controlled under physiological conditions. It has been suggested that altered epigenome and transcription dysfunction play a role in the pathogenesis of neurological disorders. Increased histone methylation, a well-established mechanism of gene silencing, results in transcriptional repression. We show that ESET expression is markedly increased in Huntington’s disease (HD) patients and in transgenic R6/2 HD mice. Similarly, the protein level of trimethylated histone H3 (K9) was also elevated in HD patients and in R6/2 HD mice. The combined pharmacological treatment with mithramycin and cystamine down-regulates ESET gene expression and reduces hypertrimethylation of histone H3 (K9). This polytherapy significantly ameliorated the behavioral and neuropathological phenotype and extended survival over 40%, well beyond any existing reported treatment in the R6/2 HD mice. Our data suggest that modulation of the epigenome, through regulation of the ESET gene is important to neuronal survival and, as such, may be a promising treatment in HD patients. In addition, administration of phenylbutyrate (PBA) increased brain histone acetylation and decreased histone methylation levels in R6/2 and N171-82Q HD mice. PBA increased mRNA for components of the ubiquitin-proteosomal pathway and down-regulated caspases implicated in apoptotic cell death, and active caspase 3 immunoreactivity in the striatum. These results show that administration of PBA, at doses that are well tolerated in man, exerts significant neuroprotective effects in transgenic mouse models of HD, and therefore represents a very promising therapeutic approach for HD. We further demonstrate that the modulation of epigenetic signaling by PBA ultimately promoted motor neuron survival and ameliorated disease progression in ALS mice. Thus, chromatin remodeling and transcriptional regulation can be a novel therapeutic target for the treatment of neurodegenerative disorders, such ALS and HD.