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1.

001-es BibID:BIBFORM029484
Első szerző:Al-Sarraj, Safa
Cím:p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS / Safa Al-Sarraj, Andrew King, Claire Troakes, Bradley Smith, Satomi Maekawa, Istvan Bodi, Boris Rogelj, Ammar Al-Chalabi, Tibor Hortobágyi, Christopher E. Shaw
Dátum:2011
ISSN:0001-6322
Megjegyzések:Neuronal cytoplasmic inclusions (NCIs) containing phosphorylated TDP-43 (p-TDP-43) are the pathological hallmarks of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and FTLD-TDP. The vast majority of NCIs in the brain and spinal cord also label for ubiquitin and p62, however, we have previously reported a subset of TDP-43 proteinopathy patients who have unusual and abundant p62 positive, TDP-43 negative inclusions in the cerebellum and hippocampus. Here we sought to determine whether these cases carry the hexanucleotide repeat expansion in C9orf72. Repeat primer PCR was performed in 36 MND/ALS, FTLD-MND/ALS and FTLD-TDP cases and four controls. Fourteen individuals with the repeat expansion were detected. In all the 14 expansion mutation cases there were abundant globular and star-shaped p62 positive NCIs in the pyramidal cell layer of the hippocampus, the vast majority of which were p-TDP-43 negative. p62 positive NCIs were also abundant in the cerebellar granular and molecular layers in all cases and in Purkinje cells in 12/14 cases but they were only positive for p-TDP-43 in the granular layer of one case. Abundant p62 positive, p-TDP-43 negative neuronal intranuclear inclusions (NIIs) were seen in 12/14 cases in the pyramidal cell layer of the hippocampus and in 6/14 cases in the cerebellar granular layer. This unusual combination of inclusions appears pathognomonic for C9orf72 repeat expansion positive MND/ALS and FTLD-TDP which we believe form a pathologically distinct subset of TDP-43 proteinopathies. Our results suggest that proteins other than TDP-43 are binding p62 and aggregating in response to the mutation which may play a mechanistic role in neurodegeneration.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
külföldön készült közlemény
Megjelenés:Acta Neuropathologica. - 122 : 6 (2011), p. 691-702. -
További szerzők:King, Andrew Troakes, Claire Smith, Bradley Maekawa, Satomi Bódi István (1967-) (neuropatológus) Rogelj, Boris Al-Chalabi, Ammar Shaw, Christopher E. Hortobágyi Tibor (1965-) (patológus)
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2.

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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3.

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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4.

001-es BibID:BIBFORM076126
035-os BibID:(WoS)000446548400016 (Scopus)85054395402
Első szerző:Solomon, Daniel A.
Cím:A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-[alfa] mediates C9orf72-related neurodegeneration / Solomon Daniel A., Stepto Alan., Au Wing Hei, Adachi Yoshitsugu, Diaper Danielle C., Hall Rachel, Rekhi Anjeet, Boudi Adel, Tziortzouda Paraskevi, Lee Youn-Bok, Smith Bradley, Bridi Jessika C., Spinelli Greta, Dearlove Jonah, Humphrey Dickon M., Gallo Jean-Marc, Troakes Claire, Fanto Manolis, Soller Matthias, Rogelj Boris, Parsons Richard B., Shaw Christopher E., Hortobágyi Tibor, Hirth Frank
Dátum:2018
ISSN:0006-8950
Megjegyzések:Accumulation and aggregation of TDP-43 is a major pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 inclusions also characterize patients with GGGGCC (G4C2) hexanucleotide repeat expansion in C9orf72 that causes the most common genetic form of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Functional studies in cell and animal models have identified pathogenic mechanisms including repeat-induced RNA toxicity and accumulation of G4C2-derived dipeptide-repeat proteins. The role of TDP-43 dysfunction in C9ALS/FTD, however, remains elusive. We found G4C2-derived dipeptide-repeat protein but not G4C2-RNA accumulation caused TDP-43 proteinopathy that triggered onset and progression of disease in Drosophila models of C9ALS/FTD. Timing and extent of TDP-43 dysfunction was dependent on levels and identity of dipeptide-repeat proteins produced, with poly-GR causing early and poly-GA/poly-GP causing late onset of disease. Accumulating cytosolic, but not insoluble aggregated TDP-43 caused karyopherin-?2/4 (KPNA2/4) pathology, increased levels of dipeptide-repeat proteins and enhanced G4C2-related toxicity. Comparable KPNA4 pathology was observed in both sporadic frontotemporal dementia and C9ALS/FTD patient brains characterized by its nuclear depletion and cytosolic accumulation, irrespective of TDP-43 or dipeptide-repeat protein aggregates. These findings identify a vicious feedback cycle for dipeptide-repeat protein-mediated TDP-43 and subsequent KPNA pathology, which becomes self-sufficient of the initiating trigger and causes C9-related neurodegeneration.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Brain. - 141 : 10 (2018), p. 2908-2924. -
További szerzők:Stepto, Alan Au, Wing Hei Adachi, Yoshitsugu Diaper, Danielle C. Hall, Rachel Rekhi, Anjeet Boudi, Adel Tziortzouda, Paraskevi Lee, Younbok Smith, Bradley Bridi, Jessika C. Spinelli, Greta Dearlove, Jonah Humphrey, Dickon M. Gallo, Jean-Marc Troakes, Claire Fanto, Manolis Soller, Matthias Rogelj, Boris Parsons, Richard B. Shaw, Christopher E. Hortobágyi Tibor (1965-) (patológus) Hirth, Frank
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5.

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
külföldön készlt közlemény
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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6.

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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