Absence of heterogeneous nuclear ribonucleoproteins and survival motor neuron protein in TDP-43 positive inclusions in frontotemporal lobar degeneration.
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.
Neumann
Manuela
M
Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Feodor-Lynen-Str. 23, 81377 Munich, Germany. Manuela.Neumann@med.uni-muenchen.de
Igaz
Lionel M
LM
Kwong
Linda K
LK
Nakashima-Yasuda
Hanae
H
Kolb
Stephen J
SJ
Dreyfuss
Gideon
G
Kretzschmar
Hans A
HA
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003704:Dementia / Q000378:metabolism* / Q000473:pathology*; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D055532:SMN Complex Proteins; D025801:Ubiquitin / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D025801:Ubiquitin