Poly-A binding protein-1 localization to a subset of TDP-43 inclusions in amyotrophic lateral sclerosis occurs more frequently in patients harboring an expansion in C9orf72

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease in which the loss of spinal cord motor neurons leads to paralysis and death within a few years of clinical disease onset. In almost all cases of ALS, transactive response DNA binding protein of 43 kDa (TDP-43) forms cytoplasmic neuronal inclusions. A second causative gene for a subset of ALS is fused in sarcoma, an RNA binding protein that also forms cytoplasmic inclusions in spinal cord motor neurons. Poly-A binding protein-1 (PABP-1) is a marker of stress granules (i.e. accumulations of proteins and RNA indicative of translational arrest in cells under stress). We report on the colocalization of PABP-1 to both TDP-43 and fused-in-sarcoma inclusions in 4 patient cohorts: ALS without a mutation, ALS with an intermediate polyglutamine repeat expansion in ATXN2, ALS with a GGGGCC hexanucleotide repeat expansion in C9orf72, and ALS with basophilic inclusion body disease. Notably, PABP-1 colocalization to TDP-43 was twice as frequent in ALS with C9orf72 expansions compared to ALS with no mutation. This study highlights PABP-1 as a protein that is important to the pathology of ALS and indicates that the proteomic profile of TDP-43 inclusions in ALS may differ depending on the causative genetic mutation. © 2014 by the American Association of Neuropathologists, Inc.