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001-es BibID:	BIBFORM016356
Első szerző:	Nishimura, Agnes Lumi
Cím:	Nuclear import impairment causes cytoplasmic trans-activation response DNA-binding protein accumulation and is associated with frontotemporal lobar degeneration / Agnes L. Nishimura, Vera Zupunski, Claire Troakes, Claudia Kathe, Pietro Fratta, Michael Howell, Jean-Marc Gallo, Tibor Hortobágyi, Christopher E. Shaw, Boris Rogelj
Dátum:	2010
ISSN:	0006-8950
Megjegyzések:	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.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Brain. - 133 : 6 (2010), p. 1763-1771. -
További szerzők:	Župunski, Vera Troakes, Claire Kathe, Claudia Fratta, Pietro Howell, Michael Gallo, Jean-Marc Hortobágyi Tibor (1965-) (patológus) Shaw, Christopher E. Rogelj, Boris
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001-es BibID:	BIBFORM051631
035-os BibID:	PMID: 23474818
Első szerző:	Vance, Caroline
Cím:	ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within cytoplasmic stress granules / Caroline Vance, Emma L. Scotter, Agnes L. Nishimura, Claire Troakes, Jacqueline C. Mitchell, Claudia Kathe, Hazel Urwin, Catherine Manser, Christopher C. Miller, Tibor Hortobágyi, Mike Dragunow, Boris Rogelj, Christopher E. Shaw
Dátum:	2013
ISSN:	0964-6906
Megjegyzések:	Mutations in the gene encoding Fused in Sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. FUS is a predominantly nuclear DNA- and RNA-binding protein that is involved in RNA processing. Large FUS-immunoreactive inclusions fill the perikaryon of surviving motor neurons of ALS patients carrying mutations at post-mortem. This sequestration of FUS is predicted to disrupt RNA processing and initiate neurodegeneration. Here, we demonstrate that C-terminal ALS mutations disrupt the nuclear localizing signal (NLS) of FUS resulting in cytoplasmic accumulation in transfected cells and patient fibroblasts. FUS mislocalization is rescued by the addition of the wild-type FUS NLS to mutant proteins. We also show that oxidative stress recruits mutant FUS to cytoplasmic stress granules where it is able to bind and sequester wild-type FUS. While FUS interacts with itself directly by protein-protein interaction, the recruitment of FUS to stress granules and interaction with PABP are RNA dependent. These findings support a two-hit hypothesis, whereby cytoplasmic mislocalization of FUS protein, followed by cellular stress, contributes to the formation of cytoplasmic aggregates that may sequester FUS, disrupt RNA processing and initiate motor neuron degeneration.
Tárgyszavak:	Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Human Molecular Genetics. - 22 : 13 (2013), p. 2676-2688. -
További szerzők:	Scotter, Emma L. Nishimura, Agnes Lumi Troakes, Claire Mitchell, Jacqueline C. Kathe, Claudia Urwin, Hazel Manser, Catherine Miller, Christopher C. Hortobágyi Tibor (1965-) (patológus) Dragunow, Mike Rogelj, Boris Shaw, Christopher E.
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