The nuclear poly(A) binding protein 1 (PABPN1) is a ubiquitously expressed protein that plays critical roles at multiple steps in post-transcriptional regulation of gene expression. Short expansions of the polyalanine tract in the N-terminus of PABPN1 lead to Oculopharyngeal Muscular Dystrophy (OPMD). Patients who suffer from OPMD have progressive weakening of specific muscles most notably those of the pharynx. Defects in pharyngeal muscle function can cause choking and regurgitation leading to pneumonia or sudden death. There is no current treatment for OPMD. Much is still unknown regarding the mechanism by which ubiquitous expression of this alanine-expanded PABPN1 leads to muscle-specific pathology. We have discovered that the steady-state levels of both PABPN1 mRNA and protein are drastically lower in mouse and human skeletal muscle, particularly those impacted in OPMD, compared to other tissues. The low levels of PABPN1 in skeletal muscle could predispose this tissue to the deleterious effects of alanine-expanded PABPN1. The low level of Pabpn1 transcript present in muscle indicates tissue-specific regulatory mechanisms at either the transcriptional or post-transcriptional level or possibly both. We find that Pabpn1 expression in different tissues is in part regulated by a post-transcriptional mechanism that modulates transcript stability but further studies are needed to fully elucidate how PABPN1 expression is controlled. The goal of this proposal is to test our working hypothesis that low levels of PABPN1 in skeletal muscle predispose this tissue to the deleterious effects of alanine-expanded PABPN1. To define the mechanisms that lead to the low levels of expression of PABPN1 in muscle, we will map the cis-elements responsible for modulating the stability of the Pabpn1 transcript in skeletal muscle (Aim 1) and identify the cellular factors (RNA binding proteins and miRNAs) that bind to the PABPN1 transcript to modulate transcript stability in a tissue-specific manner (Aim 2). In addition, we will determine whether transcriptional mechanisms contribute to the low levels of PABPN1 transcript in skeletal muscle (Aim 3). Of particular importance to OPMD, we will exploit two novel mouse models (both a PABPN1 Knockout mouse and an alanine-expanded PABPN1 Knockin mouse) that we have create to directly test whether a decrease in the level of PABPN1 exacerbates the pathology induced by alanine-expanded PABPN1 (Aim 4). The long-term goal of our studies is to understand why ubiquitous expression of mutant PABPN1 leads to a muscle-specific disease. These studies are significant as they will identify pathways that could be manipulated to improve the quality of life for patients that suffer from OPMD. Furthermore, these studies could lay the groundwork for understanding tissue-specific pathology in other diseases.

Public Health Relevance

The goal of the proposed studies is to understand why small changes in the PABPN1 protein causes a form of muscular dystrophy called oculopharyngeal muscular dystrophy, a disease that causes eyelid drooping and difficulties in swallowing that can lead to choking and malnutrition, for which there are currently no treatment options. Although people who suffer from this disease have the defective protein in all types of cells and tissues in their bodies, only specific muscles are affected. Understanding what makes the muscle tissue susceptible to the effects of the mutant proteins will allow development of therapies for this disease that target the appropriate molecular pathways and improve the quality of life for patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR061987-08
Application #
9772106
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Cheever, Thomas
Project Start
2011-09-01
Project End
2022-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Emory University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Phillips, Brittany L; Banerjee, Ayan; Sanchez, Brenda J et al. (2018) Post-transcriptional regulation of Pabpn1 by the RNA binding protein HuR. Nucleic Acids Res 46:7643-7661
Corbett, Anita H (2018) Post-transcriptional regulation of gene expression and human disease. Curr Opin Cell Biol 52:96-104
Vest, Katherine E; Phillips, Brittany L; Banerjee, Ayan et al. (2017) Novel mouse models of oculopharyngeal muscular dystrophy (OPMD) reveal early onset mitochondrial defects and suggest loss of PABPN1 may contribute to pathology. Hum Mol Genet 26:3235-3252
Banerjee, Ayan; Vest, Katherine E; Pavlath, Grace K et al. (2017) Nuclear poly(A) binding protein 1 (PABPN1) and Matrin3 interact in muscle cells and regulate RNA processing. Nucleic Acids Res 45:10706-10725
Randolph, Matthew E; Pavlath, Grace K (2015) A muscle stem cell for every muscle: variability of satellite cell biology among different muscle groups. Front Aging Neurosci 7:190
Randolph, Matthew E; Phillips, Brittany L; Choo, Hyo-Jung et al. (2015) Pharyngeal Satellite Cells Undergo Myogenesis Under Basal Conditions and Are Required for Pharyngeal Muscle Maintenance. Stem Cells 33:3581-95
Vest, Katherine E; Apponi, Luciano H; Banerjee, Ayan et al. (2015) An Antibody to Detect Alanine-Expanded PABPN1: A New Tool to Study Oculopharyngeal Muscular Dystrophy. J Neuromuscul Dis 2:439-446
Randolph, Matthew E; Luo, Qingwei; Ho, Justin et al. (2014) Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region-dependent manner. J Physiol 592:5301-15
Apponi, Luciano H; Corbett, Anita H; Pavlath, Grace K (2013) Control of mRNA stability contributes to low levels of nuclear poly(A) binding protein 1 (PABPN1) in skeletal muscle. Skelet Muscle 3:23
Banerjee, Ayan; Apponi, Luciano H; Pavlath, Grace K et al. (2013) PABPN1: molecular function and muscle disease. FEBS J 280:4230-50

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