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

Leeanne McGurk, Virginia M. Lee, John Q. Trojanowksi, Vivianna M. Van Deerlin, Edward B. Lee, Nancy M. Bonini (Lead / Corresponding author)

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)837-845
Number of pages9
JournalJournal of Neuropathology and Experimental Neurology
Volume73
Issue number9
DOIs
Publication statusPublished - 1 Sep 2014

Keywords

  • Amyotrophic lateral sclerosis
  • ATXN2
  • C9orf72
  • FUS
  • Inclusion
  • Motor neuron
  • PABP-1
  • Stress granule
  • TDP-43

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