Acta Neuropathologica

, Volume 124, Issue 5, pp 733–747

Co-aggregation of RNA binding proteins in ALS spinal motor neurons: evidence of a common pathogenic mechanism

  • Brian A. Keller
  • Kathryn Volkening
  • Cristian A. Droppelmann
  • Lee Cyn Ang
  • Rosa Rademakers
  • Michael J. Strong
Original Paper

DOI: 10.1007/s00401-012-1035-z

Cite this article as:
Keller, B.A., Volkening, K., Droppelmann, C.A. et al. Acta Neuropathol (2012) 124: 733. doi:10.1007/s00401-012-1035-z

Abstract

While the pathogenesis of amyotrophic lateral sclerosis (ALS) remains to be clearly delineated, there is mounting evidence that altered RNA metabolism is a commonality amongst several of the known genetic variants of the disease. In this study, we evaluated the expression of 10 ALS-associated proteins in spinal motor neurons (MNs) in ALS patients with mutations in C9orf72 (C9orf72GGGGCC-ALS; n = 5), SOD1 (mtSOD1-ALS; n = 9), FUS/TLS (mtFUS/TLS-ALS; n = 2), or TARDBP (mtTDP-43-ALS; n = 2) and contrasted these to cases of sporadic ALS (sALS; n = 4) and familial ALS without known mutations (fALS; n = 2). We performed colorimetric immunohistochemistry (IHC) using antibodies against TDP-43, FUS/TLS, SOD1, C9orf72, ubiquitin, sequestosome 1 (p62), optineurin, phosphorylated high molecular weight neurofilament, peripherin, and Rho-guanine nucleotide exchange factor (RGNEF). We observed that RGNEF-immunoreactive neuronal cytoplasmic inclusions (NCIs) can co-localize with TDP-43, FUS/TLS and p62 within spinal MNs. We confirmed their capacity to interact by co-immunoprecipitations. We also found that mtSOD1-ALS cases possess a unique IHC signature, including the presence of C9orf72-immunoreactive diffuse NCIs, which allows them to be distinguished from other variants of ALS at the level of light microscopy. These findings support the hypothesis that alterations in RNA metabolism are a core pathogenic pathway in ALS. We also conclude that routine IHC-based analysis of spinal MNs may aid in the identification of families not previously suspected to harbor SOD1 mutations.

Keywords

Amyotrophic lateral sclerosisSuperoxide dismutaseRGNEFC9orf72UbiquitinationRNA binding proteins

Supplementary material

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Brian A. Keller
    • 1
    • 2
  • Kathryn Volkening
    • 2
    • 3
  • Cristian A. Droppelmann
    • 2
  • Lee Cyn Ang
    • 1
  • Rosa Rademakers
    • 4
  • Michael J. Strong
    • 2
    • 3
    • 5
  1. 1.Department of PathologyWestern UniversityLondonCanada
  2. 2.Molecular Brain Research GroupRobarts Research InstituteLondonCanada
  3. 3.Department of Clinical Neurological SciencesWestern UniversityLondonCanada
  4. 4.Department of NeuroscienceMayo Clinic College of MedicineJacksonvilleUSA
  5. 5.LondonCanada