Volume 8 Supplement 1

Molecular Neurodegeneration: Basic biology and disease pathways

Open Access

Analysis of TDP-43 and its binding partners in neurodegenerative diseases

  • Wejdan Kattuah1,
  • Claire Troakes1,
  • Tibor Hortobagyi2,
  • Boris Rogelj3 and
  • Christopher Shaw1
Molecular Neurodegeneration20138(Suppl 1):P23

https://doi.org/10.1186/1750-1326-8-S1-P23

Published: 13 September 2013

Background

Transactive DNA binding protein (TDP-43) is the major component of the ubiquitin-positive protein aggregates seen in ~90% of Amyotrophic Lateral Sclerosis (ALS) and 60% of Frontotemporal Lobar Degeneration (FTLD) cases [1]. We have previously shown that mutations in the gene encoding TDP-43 are causally linked to familial ALS+/-FTLD [2] TDP-43 belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins that are involved in the regulation of RNA transcription, splicing, transport and translation [3]. There are a large number of hnRNPs, many of which have overlapping functions and often act cooperatively in RNA processing. Here we sought to determine whether TDP-43 aggregates contain other hnRNPs that might contribute to the neurodegenerative process.

Materials and methods

Immunohistochemistry for 14 hnRNPs predicted to associate with TDP-43 were examined in brain and spinal cord tissues from 20 FTLD-TDP and ALS cases. Co-localization with TDP-43 was examined using double-labelling immunoflouresence. Expression of selected hnRNPs was then examined in other neurodegenerative cases and controls to determine the specificity of any changes observed.

Results

One hnRNP demonstrated a striking accumulation within dystrophic neurites and cytoplasmic inclusions in the frontal cortex of FTLD-TDP cases. The hnRNP inclusions were not detected in other neurodegenerative cases with mutations of MAPT, FUS, SOD1 and C9ORF72. This particular hnRNP was found to co-localize with ~85% of TDP-43 inclusions and ~67% of ubiquitin incluions, largely in the frontal cortex and hippocampus of FTLD-TDP cases. Interestingly, the inclusions were not seen in FTLD-TDP cases with C9ORF72 mutation.

Conclusions

We have identified one hnRNP that is abundant within the inclusions seen in FTLD-TDP cases. The hnRNP is seen to colocalize with TDP-43 in the majority of cytoplasmic inclusions in FTLD-TDP but not other neurodegenerative disorders. The mechanistic implications of this interaction with TDP-43 and the contribution of its sequestration into inclusions towards neurodegeneration requires further investigation.

Authors’ Affiliations

(1)
Department of Clinical Neuroscience, Institute of Psychiatry, King’s College London
(2)
Department of Neuropathology, Institute of Pathology, Medical and Health Science Centre, University of Debrecen
(3)
Department of Biotechnology B3, Jozef Stefan Institute

References

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Copyright

© Kattuah et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.