Expression of the RNA binding protein, PABPN1, is regulated by insulin in muscle cells: Implication for oculopharyngeal muscular dystrophy Open Access

Sands, Jenna (Spring 2018)

Permanent URL: https://etd.library.emory.edu/concern/etds/mp48sc80p?locale=en
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Abstract

Oculopharyngeal muscular dystrophy (OPMD) is a late onset muscular dystrophy characterized by drooping eyelids, difficulty swallowing, and loss of mobility caused by weakness in eyelid, pharyngeal, and proximal limb muscles. The cause of OPMD is an autosomal dominant GCN expansion mutation in the PABPN1 gene, which encodes the ubiquitously-expressed, RNA binding protein polyadenylate-binding nuclear protein 1 (PABPN1). The GCN triplet repeat expands an N-terminal alanine tract in the PABPN1 protein. In patients with OPMD, the alanine tract expands from an existing 10 alanine tract to 11 to 18 alanines. How this remarkably modest change in a single allele of PABPN1, a gene encoding a ubiquitously-expressed protein, causes tissue-specific disease is not known. A previous study revealed that PABPN1 protein levels are much lower in skeletal muscle than in other tissues, and PABPN1 protein levels were even lower in muscled affected in OPMD. These findings suggested a loss of function model in which low PABPN1 protein levels could predispose tissue to OPMD pathology. Few studies have defined the mechanisms that modulate Pabpn1 expression. Here, we investigate three insulin regulated   pathways. These pathways are protein degradation, the mechanistic target of rapamycin pathway (mTOR) pathway that is a major regulator of translation, and the insulin/Glucose transporter type 4 pathway (GLUT4). Our preliminary results suggest that PABPN1 protein turnover is not regulated by insulin, but we uncovered interesting results about both the mTOR pathway and the GLUT4 pathway. Our work suggests that these pathways merit further investigation for potential contributions to regulation of PABPN1 expression.

Table of Contents

Introduction                     1 

Materials and Methods                   7 

Results                    11 

Discussion                   19 

References                   25

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