Nuclear import impairment causes cytoplasmic trans-activation response DNA-binding protein accumulation and is associated with frontotemporal lobar degeneration

Agnes L. Nishimura, Vera Upunski, Claire Troakes, Claudia Kathe, Pietro Fratta, Michael Howell, Jean Marc Gallo, T. Hortobágyi, Christopher E. Shaw, Boris Rogelj

Research output: Contribution to journalArticle

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Abstract

Trans-activation response DNA-binding protein (TDP-43) accumulation is the major component of ubiquitinated protein inclusions found in patients with amyotrophic lateral sclerosis, and frontotemporal lobar degeneration with TDP-43 positive ubiquitinated inclusions, recently relabelled the 'TDP-43 proteinopathies'. TDP-43 is predominantly located in the nucleus, however, in disease it mislocalizes to the cytoplasm where it aggregates to form hallmark pathological inclusions. The identification of TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis cases confirms its pathogenic role; but it is wild-type TDP-43 that is deposited in the vast majority of TDP-43 proteinopathies, implicating other unknown factors for its mislocalization and aggregation. One such mechanism may be defective nuclear import of TDP-43 protein, as a disruption of its nuclear localization signal leads to mislocalization and aggregation of TDP-43 in the cytoplasm. In order to explore the factors that regulate the nuclear import of TDP-43, we used a small interfering RNA library to silence 82 proteins involved in nuclear transport and found that knockdowns of karyopherin-β1 and cellular apoptosis susceptibility protein resulted in marked cytoplasmic accumulation of TDP-43. In glutathione S-transferase pull-down assays, TDP-43 bound to karyopherin-αs, thereby confirming the classical nuclear import pathway for the import of TDP-43. Analysis of the expression of chosen nuclear import factors in post-mortem brain samples from patients with TDP-43 positive frontotemporal lobar degeneration, and spinal cord samples from patients with amyotrophic lateral sclerosis, revealed a considerable reduction in expression of cellular apoptosis susceptibility protein in frontotemporal lobar degeneration. We propose that cellular apoptosis susceptibility protein associated defective nuclear transport may play a mechanistic role in the pathogenesis of the TDP-43 positive frontotemporal lobar degeneration.

Original languageEnglish
Pages (from-to)1763-1771
Number of pages9
JournalBrain
Volume133
Issue number6
DOIs
Publication statusPublished - Jun 2010

Fingerprint

Frontotemporal Lobar Degeneration
Cell Nucleus Active Transport
DNA-Binding Proteins
Cellular Apoptosis Susceptibility Protein
TDP-43 Proteinopathies
Karyopherins
Amyotrophic Lateral Sclerosis
Cytoplasm
Ubiquitinated Proteins
Nuclear Localization Signals
Glutathione Transferase
Small Interfering RNA
Spinal Cord
Proteins
Mutation
Brain

Keywords

  • Cellular apoptosis susceptibility
  • Frontotemporal lobar degeneration
  • Karyopherin-β1
  • Nuclear transport
  • TDP-43

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Nuclear import impairment causes cytoplasmic trans-activation response DNA-binding protein accumulation and is associated with frontotemporal lobar degeneration. / Nishimura, Agnes L.; Upunski, Vera; Troakes, Claire; Kathe, Claudia; Fratta, Pietro; Howell, Michael; Gallo, Jean Marc; Hortobágyi, T.; Shaw, Christopher E.; Rogelj, Boris.

In: Brain, Vol. 133, No. 6, 06.2010, p. 1763-1771.

Research output: Contribution to journalArticle

Nishimura, AL, Upunski, V, Troakes, C, Kathe, C, Fratta, P, Howell, M, Gallo, JM, Hortobágyi, T, Shaw, CE & Rogelj, B 2010, 'Nuclear import impairment causes cytoplasmic trans-activation response DNA-binding protein accumulation and is associated with frontotemporal lobar degeneration', Brain, vol. 133, no. 6, pp. 1763-1771. https://doi.org/10.1093/brain/awq111
Nishimura, Agnes L. ; Upunski, Vera ; Troakes, Claire ; Kathe, Claudia ; Fratta, Pietro ; Howell, Michael ; Gallo, Jean Marc ; Hortobágyi, T. ; Shaw, Christopher E. ; Rogelj, Boris. / Nuclear import impairment causes cytoplasmic trans-activation response DNA-binding protein accumulation and is associated with frontotemporal lobar degeneration. In: Brain. 2010 ; Vol. 133, No. 6. pp. 1763-1771.
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abstract = "Trans-activation response DNA-binding protein (TDP-43) accumulation is the major component of ubiquitinated protein inclusions found in patients with amyotrophic lateral sclerosis, and frontotemporal lobar degeneration with TDP-43 positive ubiquitinated inclusions, recently relabelled the 'TDP-43 proteinopathies'. TDP-43 is predominantly located in the nucleus, however, in disease it mislocalizes to the cytoplasm where it aggregates to form hallmark pathological inclusions. The identification of TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis cases confirms its pathogenic role; but it is wild-type TDP-43 that is deposited in the vast majority of TDP-43 proteinopathies, implicating other unknown factors for its mislocalization and aggregation. One such mechanism may be defective nuclear import of TDP-43 protein, as a disruption of its nuclear localization signal leads to mislocalization and aggregation of TDP-43 in the cytoplasm. In order to explore the factors that regulate the nuclear import of TDP-43, we used a small interfering RNA library to silence 82 proteins involved in nuclear transport and found that knockdowns of karyopherin-β1 and cellular apoptosis susceptibility protein resulted in marked cytoplasmic accumulation of TDP-43. In glutathione S-transferase pull-down assays, TDP-43 bound to karyopherin-αs, thereby confirming the classical nuclear import pathway for the import of TDP-43. Analysis of the expression of chosen nuclear import factors in post-mortem brain samples from patients with TDP-43 positive frontotemporal lobar degeneration, and spinal cord samples from patients with amyotrophic lateral sclerosis, revealed a considerable reduction in expression of cellular apoptosis susceptibility protein in frontotemporal lobar degeneration. We propose that cellular apoptosis susceptibility protein associated defective nuclear transport may play a mechanistic role in the pathogenesis of the TDP-43 positive frontotemporal lobar degeneration.",
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