Mitochondrial Dysfunction Reveals the Role of mRNA Poly(A) Tail Regulation in Oculopharyngeal Muscular Dystrophy Pathogenesis

Oculopharyngeal muscular dystrophy (OPMD), a late-onset disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-regulated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correlates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the Drosophila OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-regulated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative disorders that involve mitochondrial dysfunction.
Author Summary Oculopharyngeal muscular dystrophy is a genetic disease characterized by progressive degeneration of specific muscles, leading to ptosis (eyelid drooping), dysphagia (swallowing difficulties) and proximal limb weakness. The disease results from mutations in a nuclear protein called poly(A) binding protein nuclear 1 that is involved in polyadenylation of messenger RNAs (mRNAs) and poly(A) site selection. To address the molecular mechanisms involved in the disease, we have used two animal models (Drosophila and mouse) that recapitulate the features of this disorder. We show that oculopharyngeal muscular dystrophy pathogenesis depends on defects in poly(A) tail length regulation of specific mRNAs. Because poly(A) tails play an essential role in mRNA stability, these defects result in accelerated decay of these mRNAs. The affected mRNAs encode mitochondrial proteins, and mitochondrial activity is impaired in diseased muscles. These findings have important implications for the development of potential therapies for oculopharyngeal muscular dystrophy, and might be relevant to decipher the molecular mechanisms underlying other disorders that involve mitochondrial dysfunction.