Acta Neuropathologica

, Volume 113, Issue 5, pp 543–548

Absence of heterogeneous nuclear ribonucleoproteins and survival motor neuron protein in TDP-43 positive inclusions in frontotemporal lobar degeneration

  • Manuela Neumann
  • Lionel M. Igaz
  • Linda K. Kwong
  • Hanae Nakashima-Yasuda
  • Stephen J. Kolb
  • Gideon Dreyfuss
  • Hans A. Kretzschmar
  • John Q. Trojanowski
  • Virginia M. -Y. Lee
Original Paper

DOI: 10.1007/s00401-007-0221-x

Cite this article as:
Neumann, M., Igaz, L.M., Kwong, L.K. et al. Acta Neuropathol (2007) 113: 543. doi:10.1007/s00401-007-0221-x

Abstract

TDP-43 was recently identified as the major disease protein in neuronal inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). TDP-43 becomes redistributed from the nucleus to the cytoplasm, ubiquitinated, hyperphosphorylated and cleaved to generate C-terminal fragments, thereby linking mismetabolism of TDP-43 to the pathogenesis of FTLD-U. The function of TDP-43 is unclear, however it has been shown that TDP-43 might act as transcription repressor and activator of exon skipping through interaction with proteins of the heterogeneous nuclear ribonucleoprotein (hnRNP) family as well as a scaffold for nuclear bodies through interactions with survival motor neuron protein.

To investigate whether these binding partners might be associated with TDP-43 pathology, we studied the expression and localization of proteins of the hnRNP family (hnRNP A1, A2/B1, C1/C2) and SMN protein in affected brain regions in patients with sporadic and familial FTLD-U and normal control brains by immunohistochemistry and biochemical analysis. In contrast to TDP-43, no changes in subcellular distribution, no labeling of pathologic inclusions and no biochemical alterations were detectable for the tested hnRNPs and SMN in FTLD-U brains compared to controls. These results argue against a role of these binding partners in the pathogenesis of FTLD-U and emphasize the specificity of TDP-43 as marker for FTLD-U pathology.

Keywords

TDP-43 hnRNP SMN Ubiquitin FTD 

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Manuela Neumann
    • 1
  • Lionel M. Igaz
    • 2
  • Linda K. Kwong
    • 2
  • Hanae Nakashima-Yasuda
    • 2
  • Stephen J. Kolb
    • 4
    • 5
  • Gideon Dreyfuss
    • 4
    • 5
  • Hans A. Kretzschmar
    • 1
  • John Q. Trojanowski
    • 2
    • 3
  • Virginia M. -Y. Lee
    • 2
    • 3
  1. 1.Center for Neuropathology and Prion Research Ludwig-Maximilians UniversityMunichGermany
  2. 2.Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  3. 3.Institute on AgingUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  4. 4.Howard Hughes Medical InstituteUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  5. 5.Department of Biochemistry and Molecular BiophysicsUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

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