Histone deacetylase 4 (HDAC4), an epigenetic target for spinal muscular atrophy

Abstract

Summary. Spinal muscular atrophy, a neurodegenerative recessive disease, is one of the leading genetic causes of death in early infancy and childhood worldwide, having an etiology in a mutation or deletion of the survival motor neuron 1 gene and deficient expression of the survival motor neuron protein. Being developed, spinal muscular atrophy is manifested in the denervation and consequent overexpression of histone deacetylase 4 in skeletal muscle, an epigenetic protein further having a role in the upregulation of two E3 ligases, atrogin-1 and MuRF1 via the myogenin-dependent pathway and leading to the structural and functional muscle protein breakdown through the ubiquitin-proteasome pathway. Being not medically treated, spinal muscular atrophy can progress toward the loss of movement and even death.  Therefore, great efforts have been made so far to find an adequate therapy, with therapies already approved in Europe and the United States, yet of limited availability due to the high prices and severe side effects. In that sense, there are continuous efforts among the scientific community worldwide to develop novel, cost-efficient approaches in therapy. The development of selective histone deacetylase 4 inhibitors and their epigenetic modifying capabilities has been of high interest in an attempt to find potential candidates for the effective treatment of spinal muscular atrophy. Nevertheless, none of the histone deacetylase 4 inhibitors has been repurposed for treating spinal muscular atrophy.