Nuclear import impairment causes cytoplasmic trans-activation response DNA-binding protein accumulation and is associated with frontotemporal lobar degeneration
Autor: | Pietro Fratta, Jean-Marc Gallo, Boris Rogelj, Claire Troakes, Zupunski, Agnes L. Nishimura, Tibor Hortobágyi, Christopher Shaw, Michael Howell, Claudia Kathe |
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Rok vydání: | 2010 |
Předmět: |
Male
alpha Karyopherins Cytoplasm Pathology medicine.medical_specialty Active Transport Cell Nucleus Cell Line Mice Ubiquitin Cellular Apoptosis Susceptibility Protein Cell Line Tumor mental disorders medicine Animals Humans Elméleti orvostudományok Amyotrophic lateral sclerosis Aged Glutathione Transferase biology Amyotrophic Lateral Sclerosis Brain nutritional and metabolic diseases Orvostudományok Frontotemporal lobar degeneration Middle Aged beta Karyopherins medicine.disease nervous system diseases Cell biology DNA-Binding Proteins Cell nucleus medicine.anatomical_structure Spinal Cord biology.protein Female Neurology (clinical) Frontotemporal Lobar Degeneration Nuclear transport Nuclear localization sequence Cellular apoptosis susceptibility protein Signal Transduction |
Zdroj: | Brain. 133:1763-1771 |
ISSN: | 1460-2156 0006-8950 |
Popis: | 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-beta1 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-alphas, 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. |
Databáze: | OpenAIRE |
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