The discovery marks an important step in understanding the molecular basis of Facioscapulohumeral muscular dystrophy.
Facioscapulohumeral muscular dystrophy (FSHD) is the third most common hereditary muscular dystrophy, manifesting as muscular weakness and wasting. FSHD is slowly progressive, initially affecting facial, shoulder, and proximal upper limb muscles and continuing to lower limb muscles.
Dr Massimo Ganassi and Professor Peter Zammit, from the School of Basic & Medical Biosciences, have published new findings on a protein that may help to counteract muscle damage in FSHD in Frontiers in Cell and Developmental Biology.
It is suspected that the root cause of FSHD is a genetic mutation leading to the uncontrolled accumulation of the toxic protein DUX4, which irreversibly hampers muscle function by causing muscle cell death. However, how DUX4 alters muscle health at molecular level is not yet clear, limiting scientists' ability to develop tailored treatment for FSHD.
In addition, much preclinical and clinical endeavor is directed at suppressing ongoing DUX4 activation as a therapy, but DUX4 is notoriously difficult to detect in both FSHD muscle cells and muscle biopsies from patients. As a result, identification of alternative approaches to block effects of DUX4-mediated toxicity remains an urgent priority.
Ganassi and Zammit have discovered that DUX4c, a protein highly similar to DUX4 but not toxic, is able to antagonise and reduce DUX4's damaging effect in muscle cells, providing an alternative way to tackle FSHD.
The study also reveals that DUX4 damages muscle by disrupting WNT/β-CATENIN, a cellular signalling that must be usually finely tuned. The study shows that restoration of correct signalling, via drug treatment, also strongly reduces DUX4 toxicity and improves the viability of patient-derived cells.
These findings provide insights into the pathology in patients, indicating a molecular cause of the declining muscle function observed in FSHD, and provides possible alternative therapies to lessen disease progression.
Our study sheds light on the molecular cause of FSHD, highlighting the antagonism between DUX4 and DUX4c that converge on the regulation of WNT signalling, an essential pathway for muscle function and health. This discovery provides new insight into FSHD course and paves the way for development of more tailored therapeutic interventions"– Dr Massimo Ganassi
Driven by these findings the authors are now investigating other molecular signallings that are altered in the pathology, with an aim to better understand the causes of FSHD and contribute to developing alternative therapeutic treatments that tackle specific molecular dysfunction.
The full paper, 'Antagonism Between DUX4 and DUX4c Highlights a Pathomechanism Operating Through β-Catenin in Facioscapulohumeral Muscular Dystrophy' is published in Frontiers in Cell and Developmental Biology.'
