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Pharmacological modulation of the ER stress response ameliorates oculopharyngeal muscular dystrophy

2019; Oxford University Press; Volume: 28; Issue: 10 Linguagem: Inglês

10.1093/hmg/ddz007

1460-2083

Alberto Malerba, Fanny Roth, Pradeep Harish, Jamila Dhiab, Ngoc Lu‐Nguyen, Ornella Cappellari, Susan Jarmin, Alexandrine Mahoudeau, Victor Ythier, Jeanne Lainé, Elisa Négroni, Emmanuelle Abgueguen, Martine Simonelig, Philippe Guédat, Vincent Mouly, Gillian Butler‐Browne, Cécile Voisset, George Dickson, Capucine Trollet,

Autophagy in Disease and Therapy

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 initiation factor 2α subunit 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.