Proteomic analysis reveals that wildtype and alanine-expanded nuclear poly(A)-binding protein exhibit differential interactions in skeletal muscle

• Type of Material: Article
• Authors: Ayan Banerjee, Emory University; Brittany L. Phillips, Emory University; Quidong Deng, Emory University; Nicholas Seyfried, Emory University; Grace Pavlath, Emory University; Katherine E. Vest, University of Cincinnati; Anita Corbett, Emory University
• Language: English
• Date: 2019-05-03
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Banerjee et al.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.RA118.007287
• Title of Journal or Parent Work: Journal of Biological Chemistry
• Volume: 294
• Issue: 18
• Start Page: 7360
• End Page: 7376
• Grant/Funding Information: This work was supported by National Institutes of Health Grants 5RO1AR061987 (to A. H. C. and G. K. P.) and 5F32AR068207 (to K.E.V.) and Muscular Dystrophy Association Grants 255856 (to A. B.) and 422006 (to A. H. C.).
• Keywords: Biochemistry & Molecular Biology; protein-protein interaction; protein aggregation; poly(A) polyalanine tract; Sortilin; Inclusions; Matrin 3; TAR DNA-binding protein 43 (TDP-43) (TARDBP); proteomics; Pathogenic mechanisms; Life Sciences & Biomedicine; oculopharyngeal muscular dystrophy (OPMD); Gene; Poly(A) tail; RNA-binding protein; In-VIVO; gene regulation; PABPN1; Science & Technology; muscular dystrophy; Oculopharyngeal muscular-dystrophy; skeletal muscle; TDP-43 accumulation
• Research Categories: Chemistry, Biochemistry; Biology, Molecular; Biology, Microbiology; Biology, Genetics

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, primarily autosomal dominant disease caused by a short GCN expansion in the PABPN1 (polyadenylate-binding protein nuclear 1) gene that results in an alanine expansion at the N terminus of the PABPN1 protein. Expression of alanine-expanded PABPN1 is linked to the formation of nuclear aggregates in tissues from individuals with OPMD. However, as with other nuclear aggregate-associated diseases, controversy exists over whether these aggregates are the direct cause of pathology. An emerging hypothesis is that a loss of PABPN1 function and/or aberrant protein interactions contribute to pathology in OPMD. Here, we present the first global proteomic analysis of the protein interactions of WT and alanine-expanded PABPN1 in skeletal muscle tissue. These data provide both insight into the function of PABPN1 in muscle and evidence that the alanine expansion alters the protein-protein interactions of PABPN1. We extended this analysis to demonstrate altered complex formation with and loss of function of TDP-43 (TAR DNA-binding protein 43), which we show interacts with alanine-expanded but not WT PABPN1. The results from our study support a model where altered protein interactions with alanine-expanded PABPN1 that lead to loss or gain of function could contribute to pathology in OPMD.