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1.

001-es BibID:BIBFORM019976
Első szerző:Hortobágyi Tibor (patológus)
Cím:Optineurin inclusions occur in a minority of TDP-43 positive ALS and FTLD-TDP cases and are rarely observed in other neurodegenerative disorders / Tibor Hortobágyi, Claire Troakes, Agnes L. Nishimura, Caroline Vance, John C. van Swieten, Harro Seelaar, Andrew King, Safa Al-Sarraj, Boris Rogelj, Christopher E. Shaw
Dátum:2011
ISSN:0001-6322
Megjegyzések:Optineurin (OPTN) is a multifunctional protein involved in vesicular trafficking, signal transduction and gene expression. OPTN mutations were described in eight Japanese patients with familial and sporadic amyotrophic lateral sclerosis (FALS, SALS). OPTN-positive inclusions co-localising with TDP-43 were described in SALS and in FALS with SOD-1 mutations, potentially linking two pathologically distinct pathways of motor neuron degeneration. We have explored the abundance of OPTN inclusions using a range of antibodies in postmortem tissues from 138 cases and controls including sporadic and familial ALS, frontotemporal lobar degeneration (FTLD) and a wide range of neurodegenerative proteinopathies. OPTN-positive inclusions were uncommon and detected in only 11/32 (34%) of TDP-43-positive SALS spinal cord and 5/15 (33%) of FTLD-TDP. Western blot of lysates from FTLD-TDP frontal cortex and TDP-43-positive SALS spinal cord revealed decreased levels of OPTN protein compared to controls (p < 0.05), however, this correlated with decreased neuronal numbers in the brain. Large OPTN inclusions were not detected in FALS with SOD-1 and FUS mutation, respectively, or in FTLD-FUS cases. OPTN-positive inclusions were identified in a few Alzheimer's disease (AD) cases but did not co-localise with tau and TDP-43. Occasional striatal neurons contained granular cytoplasmic OPTN immunopositivity in Huntington's disease (HD) but were absent in spinocerebellar ataxia type 3. No OPTN inclusions were detected in FTLD-tau and α-synucleinopathy. We conclude that OPTN inclusions are relatively rare and largely restricted to a minority of TDP-43 positive ALS and FTLD-TDP cases. Our results do not support the proposition that OPTN inclusions play a central role in the pathogenesis of ALS, FTLD or any other neurodegenerative disorder.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Acta Neuropathologica. - 121 : 4 (2011), p. 519-527. -
További szerzők:Troakes, Claire Nishimura, Agnes Lumi Vance, Caroline Swieten, John C. van Seelaar, Harro King, Andrew Al-Sarraj, Safa Rogelj, Boris Shaw, Christopher E.
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2.

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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3.

001-es BibID:BIBFORM037635
Első szerző:Tollervey, James R.
Cím:Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 / Tollervey James R., Curk Tomaz, Rogelj Boris, Briese Michael, Cereda Matteo, Kayikci Melis, König Julian, Hortobágyi Tibor, Nishimura Agnes L., Zupunski Vera, Patani Rickie, Chandran Siddharthan, Rot Gregor, Zupan Blaz, Shaw Christopher E., Ule Jernej
Dátum:2011
ISSN:1097-6256
Megjegyzések:TDP-43 is a predominantly nuclear RNA-binding protein that forms inclusion bodies in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The mRNA targets of TDP-43 in the human brain and its role in RNA processing are largely unknown. Using individual nucleotide-resolution ultraviolet cross-linking and immunoprecipitation (iCLIP), we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo. Analysis of RNA binding by TDP-43 in brains from subjects with FTLD revealed that the greatest increases in binding were to the MALAT1 and NEAT1 noncoding RNAs. We also found that binding of TDP-43 to pre-mRNAs influenced alternative splicing in a similar position-dependent manner to Nova proteins. In addition, we identified unusually long clusters of TDP-43 binding at deep intronic positions downstream of silenced exons. A substantial proportion of alternative mRNA isoforms regulated by TDP-43 encode proteins that regulate neuronal development or have been implicated in neurological diseases, highlighting the importance of TDP-43 for the regulation of splicing in the brain.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Nature Neuroscience. - 14 : 4 (2011), p. 452-458. -
További szerzők:Curk, Tomaž Rogelj, Boris Briese, Michael Cereda, Matteo Kayikci, Melis König, Julian Hortobágyi Tibor (1965-) (patológus) Nishimura, Agnes Lumi Župunski, Vera Patani, Rickie Chandran, Siddharthan Rot, Gregor Zupan, Blaž Shaw, Christopher E. Ule, Jernej
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4.

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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5.

001-es BibID:BIBFORM020033
Első szerző:Vance, Caroline
Cím:Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6 / Caroline Vance, Boris Rogelj, Tibor Hortobagyi, Kurt J. De Vos, Agnes Lumi Nishimura, Jemeen Sreedharan, Xun Hu, Bradley Smith, Deborah Ruddy, Paul Wright, Jeban Ganesalingam, Kelly L. Williams, Vineeta Tripathi, Safa Al-Saraj, Ammar Al-Chalabi, P. Nigel Leigh, Ian P. Blair, Garth Nicholson, Jackie de Belleroche, Jean-Marc Gallo, Christopher C. Miller, Christopher E. Shaw
Dátum:2009
ISSN:0036-8075
Megjegyzések:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Science. - 323 : 5918 (2009), p. 1208-1211. -
További szerzők:Rogelj, Boris Hortobágyi Tibor (1965-) (patológus) De Vos, Kurt J. Nishimura, Agnes Lumi Sreedharan, Jemeen Hu, Xun Smith, Bradley Ruddy, Deborah Wright, Paul Ganesalingam, Jeban Williams, Kelly L. Tripathi, Vineeta Al-Sarraj, Safa Al-Chalabi, Ammar Leigh, P. Nigel Blair, Ian P. Nicholson, Garth de Belleroche, Jacqueline Gallo, Jean-Marc Miller, Christopher C. Shaw, Christopher E.
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