The RNA-binding motif 45 (RBM45) protein accumulates in inclusion bodies in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) patients

Mahlon Collins, David Riascos, Tina Kovalik, Jiyan An, Kelly Krupa, Kristin Krupa, Brian L. Hood, Thomas P. Conrads, Alan E. Renton, Bryan J. Traynor, Robert Bowser

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62 Scopus citations

Abstract

RNA-binding protein pathology now represents one of the best characterized pathologic features of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration patients with TDP-43 or FUS pathology (FTLD-TDP and FTLD-FUS). Using liquid chromatography tandem mass spectrometry, we identified altered levels of the RNA-binding motif 45 (RBM45) protein in the cerebrospinal fluid (CSF) of ALS patients. This protein contains sequence similarities to TAR DNA-binding protein 43 (TDP-43) and fused-in-sarcoma (FUS) that are contained in cytoplasmic inclusions of ALS and FTLDTDP or FTLD-FUS patients. To further characterize RBM45, we first verified the presence of RBM45 in CSF and spinal cord tissue extracts of ALS patients by immunoblot. We next used immunohistochemistry to examine the subcellular distribution of RBM45 and observed in a punctate staining pattern within nuclei of neurons and glia in the brain and spinal cord. We also detected RBM45 cytoplasmic inclusions in 91 % of ALS, 100 % of FTLDTDP and 75 % of Alzheimer's disease (AD) cases. The most extensive RBM45 pathology was observed in patients that harbor the C9ORF72 hexanucleotide repeat expansion. These RBM45 inclusions were observed in spinal cord motor neurons, glia and neurons of the dentate gyrus. By confocal microscopy, RBM45 co-localizes with ubiquitin and TDP-43 in inclusion bodies. In neurons containing RBM45 cytoplasmic inclusions we often detected the protein in a punctate pattern within the nucleus that lacked either TDP-43 or ubiquitin. We identified RBM45 using a proteomic screen of CSF from ALS and control subjects for candidate biomarkers, and link this RNA-binding protein to inclusion pathology in ALS, FTLD-TDP and AD.

Original languageEnglish (US)
Pages (from-to)717-732
Number of pages16
JournalActa Neuropathologica
Volume124
Issue number5
DOIs
StatePublished - Nov 2012

Bibliographical note

Funding Information:
Acknowledgments This work was supported by National Institutes of Health grants NS061867 and NS068179 to RB, a grant from the Walter S. & Lucienne Driskill Foundation to RB, and by the Achievement Rewards for College Scientists Foundation, Inc. Pittsburgh Chapter to MC. This work was also supported in part by the Intramural Research Programs of the National Institute on Aging (Z01-AG000949-02) to BJT. We thank Dr. Ronald Hamilton for neuropathologic assessment of all cases and Jonette Werley for technical assistance. The authors wish to thank the NEALS Biofluid Repository for CSF samples and all patients for their participation in this study.

Keywords

  • Amyotrophic lateral sclerosis
  • C9ORF72
  • Frontotemporal lobar degeneration
  • RBM45
  • RNA-binding protein
  • TDP-43

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