Abstract
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease that stems from mutations expanding the polyalanine tract at the N-terminus of PABPN1 [1]. This region is a trinucleotide repeat and OPMD has similarities to other trinucleotide repeat disorders like Huntington’s disease. In OPMD, symptoms include the development of intranuclear inclusions (INIs) in myocytes containing PABPN1, Hsp70, Hsp40, poly(A) RNA, ubiquitin, and proteasomes [2]. Some researchers hypothesize that the aggregates cause cellular toxicity that results in muscle degeneration [3]. Previous studies have found that the expanded polyalanine tract increases the propensity of PABPN1 to form aggregates [4]. In vitro fibril formation for synthetic peptides corresponding to the N-terminus of PABPN1 has been detected with a lag-phase that decreases as the length of the N-terminal polyalanine tract increases. There is speculation that this lag phase could be similar to the lag phase experienced by OPMD patients who do not develop symptoms until middle-age [1]. PABPN1 has been found to interact with ski-interacting protein (SKIIP) by a yeast-2-hybrid screen [5]. The binding was confirmed in vitro by immunoprecipitation and in vivo by a colocalization assay with GFP-tagged protein. PABPN1 and SKIIP were found to work together to activate E-box mediated transcription through MyoD [5]. Understanding the mechanism of onset for OPMD may lead to developing treatments and therapies for patients. Also, investigating this degenerative disease may help with research and ultimately treatments of other protein aggregation diseases such as Alzheimer’s disease, ALS, Parkinson’s disease, Huntington’s disease, and others. The research presented here examines the interaction between PABPN1 and SKIIP with the goal of localizing the region of PABPN1 that interacts with SKIIP and determining how mutations may disrupt this interaction. Mutations expanding the polyalanine tract in PABPN1 may alter the interaction between PABPN1 and SKIIP, disrupting transcription and leading to symptoms of OPMD.