Investigating proteostasis in facioscapulohumeral muscular dystrophy

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ABSTRACT Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disorder caused by complex genetic and epigenetic mechanisms. Previous studies showed that transcription de- repression of double homeobox protein 4 (DUX4) due to epigenetic changes in the D4Z4 region causes FSHD. The epigenetic changes are caused by either contraction of the D4Z4 array from 11-150 repeat units in unaffected individuals to 1-10 repeat units in roughly 95% of patients (FSHD1), or mutations in epigenetic regulators of the D4Z4 region (FSHD2). The expression of DUX4 leads to downstream molecular and cellular changes, which contribute to disease progression. Previous studies reported defects in protein degradation process in FSHD, however what proteins are affected and whether protein synthesis is affected is not clear. To study the dynamic changes in protein abundance in affected muscle cells, the research team conducted a preliminary study using liquid chromatography - tandem mass spectrometry in combination with metabolic labelling. The study identified distinct protein profiles between the myoblasts from individuals affected by FSHD and their unaffected siblings. We hypothesize that DUX4 expression is responsible for the disturbance of protein homeostasis, which contributes to the downstream molecular and cellular defects observed in FSHD. In the proposed study, we will first study the protein synthesis and degradation in immortalized FSHD myoblasts before and after a DUX4-reducing treatment. In aim 2, we will validate the in vitro findings using a xenograft mouse model. This project will discover proteins that are mis-regulated by degradative processes and synthetic processes in FSHD, which may open new opportunities for therapeutic development. The findings will also provide new insights of the disease mechanisms and evaluate the efficacy of a DUX4-reducing treatment using antisense oligonucleotides targeting the DUX4.