A protein called DUX4, incorrectly expressed in skeletal muscle fibres, is emerging as a major factor in facioscapulohumeral muscular dystrophy (FSHD). In FSHD-affected muscles, full-length DUX4 protein disrupts numerous biochemical processes and appears to inhibit the survival and regeneration of skeletal muscle fibres. Stephen Tapscott, a neurologist and molecular geneticist at the Fred Hutchinson Cancer Research Center in Seattle, was recently interviewed about the DUX4 findings and what they may mean for the FSHD community. He explains why targeting DUX4 and its downstream effects is a promising therapeutic avenue for the treatment of FSHD. In this podcast, Stephen Tapscott describes how a mutation on chromosome 4, in which repeated sequences of DNA are deleted, was identified two decades ago as the root cause of FSHD. Since then, many research groups have tried to identify the mechanism by which this deletion leads to loss of muscle tissue in FSHD. Misregulation of the DUX4 gene and inappropriate expression of the DUX4 protein were proposed early on as possible causes of FSHD, but until recently, the technology wasn't sufficient to demonstrate their involvement. It's now clear that the loss of some of the repeated DNA units on chromosome 4 causes the expression of the DUX4 protein in skeletal muscle tissue, where it's not normally expressed. The presence of DUX4 in skeletal muscle tissue may cause the death of muscle cells via a cell death program known as apoptosis. It also may cause the immune system to attack muscle fibres, and activate proteins that block normal muscle regeneration.

The Muscular Dystrophy Association's latest round of grants allocates more than $12 million to the support of 38 research projects investigating the causes of, and potential treatments for, a number of forms of neuromuscular disease. The new grants, which became effective Feb. 1, support research into more than 15 diseases in MDA's program, including Duchenne muscular dystrophy (DMD), ALS (amyotrophic lateral sclerosis or Lou Gehrig's disease), spinal muscular atrophy (SMA), facioscapulohumeral muscular dystrophy (FSHD), and others. In addition to funding investigations into underlying disease mechanisms, the grants will help guide the development of strategies for diagnosis and treatment. For example, in Pompe disease (acid maltase deficiency), scientists will look for ways to improve the current FDA-approved treatment, enzyme replacement therapy, which sometimes leads to an unwanted immune response. MDA funding also will help refine exciting experimental therapies such as exon skipping in DMD, and gene therapy in DMD and SMA. A number of the new grants are for projects using muscle stem cells, and other strategies to improve muscle regeneration and create new muscle fibres. Six grants are career development grants (DGs) designed to increase the number of scientists committed to working on neuromuscular disease research.

> For detailed information on all 38 grants, read MDA Commits $12 Million to Neuromuscular Disease Research