Linking energy metabolism to chromatin in Huntington's disease – HD-EPIeNERGY

Huntington’s disease (HD) is a rare genetic neurodegenerative disease, primarily affecting the striatum. HD neuron dysfunction starts earlier than anticipated, although early steps of the pathogenic process remain unclear. Altered energy metabolism, including reduced glucose consumption, and depleted histone acetylation at striatal identity genes are two early mechanisms observed in the HD striatum, possibly contributing to striatal dysfunction through progressive loss of striatal neuron identity. Energy metabolism and histone acetylation are tightly coordinated mechanisms. Notably, glucose metabolism controls the production of nuclear acetyl-CoA, the only donor for acetyl groups to histone acetylation. Combining epigenomics, transcriptomics, proteomics, metabolomics, stable-isotope labelling in mice and mouse genetic tools, we aim to investigate new hypothesis that impaired energy metabolism in the HD striatum underlies altered epigenetic regulation, thus contributing to pathogenesis.