Histone deacetylase 3 (HDAC3) is implicated in spinocerebellar ataxia type 1, but new data from genetic knock-in mice reveal potential risks associated with the use of HDAC inhibitors in this disease. Venkatraman et al. crossbred mice with the polyglutamine expansion seen in spinocerebellar ataxia with a strain in which HDAC3 was genetically depleted, thereby producing a mouse model of HDAC inhibition in spinocerebellar ataxia. These mice demonstrated an exaggerated disease phenotype, including early-onset ataxia and progressive degeneration of cerebellar Purkinje cells, which require HDAC3 for normal function. The results of this experiment suggest that caution is warranted when considering the use of pharmacological HDAC inhibitors in any disease, as high doses might increase the risk of damaging the cerebellum.
References
Venkatraman, A. et al. The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1. Hum. Mol. Genet. 10.1093/hmg/ddu081
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Potential adverse effects of histone deactylase inhibition in spinocerebellar ataxia type 1. Nat Rev Neurol 10, 182 (2014). https://doi.org/10.1038/nrneurol.2014.57
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DOI: https://doi.org/10.1038/nrneurol.2014.57