title: 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.
authors.affiliation: From the Department of Biology, University of Pennsylvania (LM, NMB); Translational Neuropathology Research Laboratory, Stellar Chance Laboratories (EBL); and Department of Pathology and Laboratory Medicine, Perelman School of Medicine (VML, JQT, VMVD, EBL), Philadelphia, Pennsylvania.
authors.forename: Leeanne
authors.initials: L
authors.lastname: McGurk
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowksi
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: Edward B
authors.initials: EB
authors.lastname: Lee
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology; D000067528:Ataxins; D000073885:C9orf72 Protein; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010455:Peptides / Q000235:genetics*; D039122:Poly(A)-Binding Protein I / Q000378:metabolism*; D011506:Proteins / Q000235:genetics*; D034702:RNA-Binding Protein FUS / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology*
chemical_list: D000067528:Ataxins; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D039122:Poly(A)-Binding Protein I; D011506:Proteins; D034702:RNA-Binding Protein FUS; C097188:polyglutamine
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