Pharmacological modulation of the ER stress response ameliorates oculopharyngeal muscular dystrophy

Alberto Malerba, Fanny Roth, Pradeep Harish, Jamila Dhiab, Ngoc Lu-Nguyen, Ornella Cappellari, Susan Jarmin, Alexandrine Mahoudeau, Victor Ythier, Jeanne Laine, Elisa Negroni, Emmanuelle Abgueguen, Martine Simonelig, Philippe Guedat, Vincent Mouly, Gillian Butler-Browne, Cecile Voisset, George Dickson, Capucine Trollet

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Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease leading to ptosis, dysphagia, and proximal limb muscles at later stages. A short abnormal (GCN) triplet expansion in the polyA-binding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. Here we demonstrate that treating mice with guanabenz acetate (GA), an FDA-approved antihypertensive drug, reduces the size and number of nuclear aggregates, improves muscle force, protects myofibers from the pathology-derived turnover and decreases fibrosis. GA targets various cell processes, including the unfolded protein response (UPR), which acts to attenuate endoplasmic reticulum (ER) stress. We demonstrate that GA increases both the phosphorylation of the eukaryotic translation initiator factor 2α subunit (eIF2α) and the splicing of Xbp1, key components of the UPR. Altogether these data show that modulation of protein folding regulation is beneficial for OPMD and promote the further development of GA or its derivatives for treatment of OPMD in humans. Furthermore, they support the recent evidences that treating ER stress could be therapeutically relevant in other more common proteinopathies.
Original languageEnglish
Article numberddz007
Pages (from-to)1694-1708
Number of pages15
JournalHuman Molecular Genetics
Issue number10
Early online date14 Jan 2019
Publication statusPublished - 15 May 2019

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