The normal and the polyalanine expansion mutant PABP2 have different nuclear localization patterns but show similar functions

Oculopharyngeal muscular dystrophy (OPMD) is caused by the expansion of a short (GCG) repeat from GCG₆ to GCG_8–13 in the coding region of the poly (A) binding protein 2 (PABP2) gene. PABP2 is a nuclear protein that binds to the poly (A) tail of mRNA, stimulating its extension and controlling the tail length. It is unclear why this short alanine expansion at the N-terminus of the protein can cause the typical nuclear protein aggregation and form nuclear inclusions which are the hallmark of OPMD. To help elucidate the pathological mechanism of this disease, we studied the nuclear localization pattern of either normal PABP2 or mutant PABP2 using a constitutive promoter to drive the expression of PABP2 as an N-terminal fusion protein of GFP in a mouse skeletal muscle cell culture model system. The nuclear localization of normal PABP2-GFP was found to be more diffuse with some speckle patterns, whereas the mutant PABP2 (GCG₁₃)-GFP was shown to form large bright aggregates in the nucleus. Similar aggregates were found in both muscle and non-muscle cells. Deletion of 14 amino acids residues from the C-terminus of PABP2 which contains an oligomerization domain did not abolish the aggregation property of mutant PABP2. Furthermore, protein-protein interaction and PABP2's ability to control poly (A) tail length were also studied. Results of our studies using both in vitro and in vivo assays did not detect any difference between the normal and mutant PABP2 in their ability to control poly (A) tail elongation and in their interaction with other cellular proteins.