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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:BIBFORM063335
Első szerző:Mitchell, Jacqueline C.
Cím:Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS / Jacqueline C. Mitchell, Remy Constable, Eva So, Caroline Vance, Emma Scotter, Leanne Glover, Tibor Hortobagyi, Eveline S. Arnold, Shuo-Chien Ling, Melissa McAlonis, Sandrine Da Cruz, Magda Polymenidou, Lino Tessarolo, Don W. Cleveland, Christopher E. Shaw
Dátum:2015
ISSN:2051-5960
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Acta Neuropathologica Communications. - 3 : 1 (2015), p. 1-16. -
További szerzők:Constable, Remy So, Eva Vance, Caroline Scotter, Emma L. Glover, Leanne Hortobágyi Tibor (1965-) (patológus) Arnold, Eveline S. Ling, Shuo-Chien McAlonis, Melissa Da Cruz, Sandrine Polymenidou, Magda Tessarolo, Lino Cleveland, Don W. Shaw, Christopher E.
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3.

001-es BibID:BIBFORM042979
Első szerző:Mitchell, Jacqueline C.
Cím:Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion / Jacqueline C. Mitchell, Philip McGoldrick, Caroline Vance, Tibor Hortobagyi, Jemeen Sreedharan, Boris Rogelj, Elizabeth L. Tudor, Bradley N. Smith, Christian Klasen, Christopher C. J. Miller, Jonathan D. Cooper, Linda Greensmith, Christopher E. Shaw
Dátum:2013
ISSN:0001-6322
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Acta Neuropathologica. - 125 : 2 (2013), p. 273-288. -
További szerzők:McGoldrick, Philip Vance, Caroline Hortobágyi Tibor (1965-) (patológus) Sreedharan, Jemeen Rogelj, Boris Tudor, Elizabeth L. Smith, Bradley Klasen, Christian Miller, Christopher Charles John Cooper, Jonathan D. Greensmith, Linda Shaw, Christopher E.
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4.

001-es BibID:BIBFORM051632
035-os BibID:PMID: 22692064
Első szerző:Smith, Bradley
Cím:The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder / Bradley N. Smith, Stephen Newhouse, Aleksey Shatunov, Caroline Vance, Simon Topp, Lauren Johnson, Jack Miller, Younbok Lee, Claire Troakes, Kirsten M. Scott, Ashley Jones, Ian Gray, Jamie Wright, Tibor Hortobágyi, Safa Al-Sarraj, Boris Rogelj, John Powell, Michelle Lupton, Simon Lovestone, Peter C. Sapp, Markus Weber, Peter J. Nestor, Helenius J. Schelhaas, Anneloor ALM ten Asbroek, Vincenzo Silani, Cinzia Gellera, Franco Taroni, Nicola Ticozzi, Leonard Van den Berg, Jan Veldink, Phillip Van Damme, Wim Robberecht, Pamela J. Shaw, Janine Kirby, Hardev Pall, Karen E. Morrison, Alex Morris, Jacqueline de Belleroche, J. M. B. Vianney de Jong, Frank Baas, Peter M. Andersen, John Landers, Robert H. Brown Jr., Michael E. Weale, Ammar Al-Chalabi, Christopher E. Shaw
Dátum:2013
ISSN:1018-4813
Megjegyzések:A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:European Journal of Human Genetics. - 21 : 1 (2013), p. 102-108. -
További szerzők:Newhouse, Stephen Shatunov, Aleksey Vance, Caroline Topp, Simon Johnson, Lauren Miller, Jack Lee, Younbok Troakes, Claire Scott, Kirsten M. Jones, Ashley Gray, Ian Wright, Jamie Hortobágyi Tibor (1965-) (patológus) Al-Sarraj, Safa Rogelj, Boris Powell, John Lupton, Michelle Lovestone, Simon Sapp, Peter C. Weber, Markus Nestor, Peter J. Schelhaas, Helenius J. Asbroek, Anneloor ALM ten Silani, Vincenzo Gellera, Cinzia Taroni, Franco Ticozzi, Nicola Van den Berg, Leonard H. Veldink, Jan H. Van Damme, Phillip Robberecht, Wim Shaw, Pamela J. Kirby, Janine Pall, Hardev Morrison, Karen E. Morris, Alex de Belleroche, Jacqueline Vianney de Jong, J. M. B. Baas, Frank Andersen, Peter M. Landers, John Brown, Robert H. (Jr.) Weale, Michael E. Al-Chalabi, Ammar Shaw, Christopher E.
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5.

001-es BibID:BIBFORM051599
035-os BibID:PMID: 22934812
Első szerző:Troakes, Claire
Cím:Transportin 1 colocalization with Fused in Sarcoma (FUS) inclusions is not characteristic for amyotrophic lateral sclerosis-FUS confirming disrupted nuclear import of mutant FUS and distinguishing it from frontotemporal lobar degeneration with FUS inclusions / C. Troakes, T. Hortobágyi, C. Vance, S. Al-Sarraj, B. Rogelj, C. E. Shaw
Dátum:2013
ISSN:0305-1846
Megjegyzések:AIMS: Transportin 1 (TNPO 1) is an abundant component of the Fused in Sarcoma (FUS)-immunopositive inclusions seen in a subgroup of frontotemporal lobar degeneration (FTLD-FUS). TNPO 1 has been shown to bind to the C-terminal nuclear localizing signal (NLS) of FUS and mediate its nuclear import. Amyotrophic lateral sclerosis (ALS)-linked C-terminal mutants disrupt TNPO 1 binding to the NLS and impair nuclear import in cell culture. If this held true for human ALS then we predicted that FUS inclusions in patients with C-terminal FUS mutations would not colocalize with TNPO 1. METHODS: Expression of TNPO 1 and colocalization with FUS was studied in the frontal cortex of FTLD-FUS (n = 3) and brain and spinal cord of ALS-FUS (n = 3), ALS-C9orf72 (n = 3), sporadic ALS (n = 7) and controls (n = 7). Expression levels and detergent solubility of TNPO 1 was measured by Western blot. RESULTS: Aggregates of TNPO 1 were abundant and colocalized with FUS inclusions in the cortex of all FTLD-FUS cases. In contrast, no TNPO 1-positive aggregates or FUS colocalization was evident in two-thirds, ALS-FUS cases and was rare in one ALS-FUS case. Nor were they present in C9orf72 or sporadic ALS. No increase in the levels of TNPO 1 was seen in Western blots of spinal cord tissues from all ALS cases compared with controls. CONCLUSIONS: These findings confirm that C-terminal FUS mutations prevent TNPO 1 binding to the NLS, inhibiting nuclear import and promoting cytoplasmic aggregation. The presence of TNPO 1 in wild-type FUS aggregates in FTLD-FUS distinguishes the two pathologies and implicates different disease mechanisms.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Neuropathology and Applied Neurobiology. - 39 : 5 (2013), p. 553-561. -
További szerzők:Hortobágyi Tibor (1965-) (patológus) Vance, Caroline Al-Sarraj, Safa Rogelj, Boris Shaw, Christopher E.
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6.

001-es BibID:BIBFORM029485
Első szerző:Troakes, Claire
Cím:An MND/ALS phenotype associated with C9orf72 repeat expansion : abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline / Claire Troakes, Satomi Maekawa, Lokesh Wijesekera, Boris Rogelj, László Siklós, Christopher Bell, Bradley Smith, Stephen Newhouse, Caroline Vance, Lauren Johnson, Tibor Hortobágyi, Aleksey Shatunov, Ammar Al-Chalabi, Nigel Leigh, Christopher E. Shaw, Andrew King, Safa Al-Sarraj
Dátum:2012
ISSN:0919-6544
Megjegyzések:The transactive response DNA binding protein (TDP-43) proteinopathies describe a clinico-pathological spectrum of multi-system neurodegeneration that spans motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and frontotemporal lobar degeneration (FTLD). We have identified four male patients who presented with the clinical features of a pure MND/ALS phenotype (without dementia) but who had distinctive cortical and cerebellar pathology that was different from other TDP-43 proteinopathies. All patients initially presented with weakness of limbs and respiratory muscles and had a family history of MND/ALS. None had clinically identified cognitive decline or dementia during life and they died between 11 and 32 months after symptom onset. Neuropathological investigation revealed lower motor neuron involvement with TDP-43-positive inclusions typical of MND/ALS. In contrast, the cerebral pathology was atypical, with abundant star-shaped p62-immunoreactive neuronal cytoplasmic inclusions in the cerebral cortex, basal ganglia and hippocampus, while TDP-43-positive inclusions were sparse. This pattern was also seen in the cerebellum where p62-positive, TDP-43-negative inclusions were frequent in granular cells. Western blots of cortical lysates, in contrast to those of sporadic MND/ALS and FTLD-TDP, showed high p62 levels and low TDP-43 levels with no high molecular weight smearing. MND/ALS-associated SOD1, FUS and TARDBP gene mutations were excluded; however, further investigations revealed that all four of the cases did show a repeat expansion of C9orf72, the recently reported cause of chromosome 9-linked MND/ALS and FTLD. We conclude that these chromosome 9-linked MND/ALS cases represent a pathological sub-group with abundant p62 pathology in the cerebral cortex, hippocampus and cerebellum but with no significant associated cognitive decline.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
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Megjelenés:Neuropathology. - 32 : 5 (2012), p. 505-514. -
További szerzők:Maekawa, Satomi Wijesekera, Lokesh Rogelj, Boris Siklós László Bell, Christopher Smith, Bradley Newhouse, Stephen Vance, Caroline Johnson, Lauren Shatunov, Aleksey Al-Chalabi, Ammar Leigh, P. Nigel Shaw, Christopher E. King, Andrew Al-Sarraj, Safa Hortobágyi Tibor (1965-) (patológus)
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7.

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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8.

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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