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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:BIBFORM082378
035-os BibID:(cikkazonosító)5 (WoS)000455320300001 (Scopus)85059798236
Első szerző:Ashton, Nicholas J.
Cím:Increased plasma neurofilament light chain concentration correlates with severity of post-mortem neurofibrillary tangle pathology and neurodegeneration / Nicholas J. Ashton, Antoine Leuzy, Yau Mun Lim, Claire Troakes, Tibor Hortobágyi, Kina Höglund, Dag Aarsland, Simon Lovestone, Michael Schöll, Kaj Blennow, Henrik Zetterberg, Abdul Hye
Dátum:2019
ISSN:2051-5960
Megjegyzések:Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid- (A) plaques, neurofibrillary tangles and widespread neuronal loss in the brain. In recent years, blood biomarkers have emerged as a realistic prospect to highlight accumulating pathology for secondary prevention trials. Neurofilament light chain (NfL), a marker of axonal degeneration, is robustly elevated in the blood of many neurological and neurodegenerative conditions, including AD. A strong relationship with cerebrospinal fluid (CSF) NfL suggests that these biomarker modalities reflect the same pathological process. Yet, the connection between blood NfL and brain tissue pathology has not been directly compared. In this study, longitudinal plasma NfL from cognitively healthy controls (n=12) and AD participants (n=57) were quantified by the Simoa platform. On reaching post-mortem, neuropathological assessment was performed on all participants, with additional frozen and paraffin-embedded tissue acquired from 26 participants for further biochemical (A(1-42), A(1-40), tau) and histological (NfL) evaluation. Plasma NfL concentrations were significantly increased in AD and correlated with cognitive decline, independent of age. Retrospective stratification based on Braak staging revealed that baseline plasma NfL concentrations were associated with higher neurofibrillary tangle pathology at post-mortem. Longitudinal increases in plasma NfL were observed in all Braak groupings; a significant negative association, however, was found between plasma NfL at time point 1 and both its rate of change and annual percentage increase. Immunohistochemical evaluation of NfL in the medial temporal gyrus (MTG) demonstrated an inverse relationship between Braak stages and NfL staining. Importantly, a significant negative correlation was found between the plasma NfL measurement closest to death and the level of NfL staining in the MTG at post-mortem. For the first time, we demonstrate that plasma NfL associates with the severity of neurofibrillary tangle pathology and neurodegeneration in the post-mortem brain.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Acta Neuropathologica Communications. - 7 : 1 (2019), p. 1-11. -
További szerzők:Leuzy, Antoine Lim, Yau Mun Troakes, Claire Hortobágyi Tibor (1965-) (patológus) Höglund, Kina Aarsland, Dag Lovestone, Simon Schöll, Michael Blennow, Kaj Zetterberg, Henrik Hye, Abdul
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3.

001-es BibID:BIBFORM016359
Első szerző:Buonocore, Frederica
Cím:Effects of cis-regulatory variation differ across regions of the adult human brain / Frederica Buonocore, Matthew J. Hill, Colin D. Campbell, Paul B. Oladimeji, Aaron R. Jeffries, Claire Troakes, Tibor Hortobagyi, Brenda P. Williams, Jonathan D. Cooper, Nicholas J. Bray
Dátum:2010
ISSN:0964-6906
Megjegyzések:Cis-regulatory variation is considered to be an important determinant of human phenotypic variability, including susceptibility to complex disease. Recent studies have shown that the effects of cis-regulatory polymorphism on gene expression can differ widely between tissues. In the present study, we tested whether the effects of cis-regulatory variation can also differ between regions of the adult human brain. We used relative allelic expression to measure cis-effects on the RNA expression of five candidate genes for neuropsychiatric illness (ZNF804A, NOS1, RGS4, AKT1 and TCF4) across multiple discrete brain regions within individual subjects. For all five genes, we observed significant differences in allelic expression between brain regions in several individual subjects, suggesting regional differences in the effects of cis-regulatory polymorphism to be a common phenomenon. As well as highlighting an important caveat for studies of regulatory polymorphism in the brain, our findings indicate that it is possible to delineate brain areas in which cis-regulatory variants are active. This may provide important insights into the fundamental biology of neuropsychiatric phenotypes with which such variants are associated.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Human Molecular Genetics. - 19 : 22 (2010), p. 4490-4496. -
További szerzők:Hill, Matthew J. Campbell, Colin D. Oladimeji, Paul B. Jeffries, Aaron R. Troakes, Claire Hortobágyi Tibor (1965-) (patológus) Williams, Brenda P. Cooper, Jonathan D. Bray, Nicholas J.
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4.

001-es BibID:BIBFORM019979
Első szerző:Engmann, Olivia
Cím:Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition / Olivia Engmann, Tibor Hortobágyi, Ruth Pidsley, Claire Troakes, Hans-Gert Bernstein, Michael R. Kreutz, Jonathan Mill, Margareta Nikolic, Karl Peter Giese
Dátum:2011
ISSN:0006-8950
Megjegyzések:Cyclin-dependent kinase 5 is activated by small subunits, of which p35 is the most abundant. The functions of cyclin-dependent kinase 5 signalling in cognition and cognitive disorders remains unclear. Here, we show that in schizophrenia, a disorder associated with impaired cognition, p35 expression is reduced in relevant brain regions. Additionally, the expression of septin 7 and OPA1, proteins downstream of truncated p35, is decreased in schizophrenia. Mimicking a reduction of p35 in heterozygous knockout mice is associated with cognitive endophenotypes. Furthermore, a reduction of p35 in mice results in protein changes similar to schizophrenia post-mortem brain. Hence, heterozygous p35 knockout mice model both cognitive endophenotypes and molecular changes reminiscent of schizophrenia. These changes correlate with reduced acetylation of the histone deacetylase 1 target site H3K18 in mice. This site has previously been shown to be affected by truncated p35. By restoring H3K18 acetylation with the clinically used specific histone deacetylase 1 inhibitor MS-275 both cognitive and molecular endophenotypes of schizophrenia can be rescued in p35 heterozygous knockout mice. In summary, we suggest that reduced p35 expression in schizophrenia has an impact on synaptic protein expression and cognition and that these deficits can be rescued, at least in part, by the inhibition of histone deacetylase 1.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Brain. - 134 : 8 (2011), p. 2408-2421. -
További szerzők:Hortobágyi Tibor (1965-) (patológus) Pidsley, Ruth Troakes, Claire Bernstein, Hans-Gert Kreutz, Michael R. Mill, Jonathan Nikolic, Margareta Giese, Karl Peter
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5.

001-es BibID:BIBFORM019968
Első szerző:Engmann, Olivia
Cím:Cyclin-dependent kinase 5 activator p25 is generated during memory formation and is reduced at an early stage in Alzheimer's disease / Olivia Engmann, Tibor Hortobágyi, Andrew J. Thompson, Jennifer Guadagno, Claire Troakes, Salvador Soriano, Safa Al-Sarraj, Yong Kim, Karl Peter Giese
Dátum:2011
ISSN:0006-3223
Megjegyzések:BACKGROUND: The cyclin-dependent kinase 5 activator p35 can be cleaved into p25. Formation of p25 has been suggested to contribute to neurodegeneration in Alzheimer's disease (AD). However, overexpression of low levels of p25 in mice enhances memory formation. Therefore, it has been suggested that p25 formation might be an event early in AD to compensate for impairments in synaptic plasticity. Ongoing p25 formation has been hypothesized to contribute to neurodegeneration at the later stages of AD. METHODS: Here, we tested the early compensation hypothesis by analyzing the levels of p25 and its precursor p35 in AD postmortem samples from different brain regions at different stages of tau pathology, using quantitative Western blots. Furthermore, we studied p35 and p25 during spatial memory formation. By employing quantitative mass spectrometry, we identified proteins downstream of p25, which were then studied in AD samples. RESULTS: We found that p25 is generated during spatial memory formation. Furthermore, we demonstrate that overexpression of p25 in the physiological range increases the expression of two proteins implicated in spine formation, septin 7 and optic atrophy 1. We show that the expression of p35 and p25 is reduced as an early event in AD. Moreover, expression of the p25-regulated protein optic atrophy 1 was reduced in a time course similar to p25 expression. CONCLUSIONS: Our findings suggest that p25 generation is a mechanism underlying hippocampal memory formation that is impaired in the early stages of AD. Our findings argue against the previously raised early compensation hypothesis and they propose that p25-mediated neurotoxicity does not occur in AD.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Biological Psychiatry. - 70 : 2 (2011), p. 159-168. -
További szerzők:Hortobágyi Tibor (1965-) (patológus) Thompson, Andrew J. Guadagno, Jennifer Troakes, Claire Soriano, Salvador Al-Sarraj, Safa Kim, Yong Giese, Karl Peter
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6.

001-es BibID:BIBFORM104888
035-os BibID:(scopus)85139495970 (wos)000865383100001 (cikkazonosító)e12852
Első szerző:Glebov, Oleg O.
Cím:Structural synaptic signatures of Alzheimer's disease and dementia with Lewy bodies in the male brain / Glebov Oleg O., Williamson David, Owen Dylan M., Hortobágyi Tibor, Troakes Claire, Aarsland Dag
Dátum:2023
ISSN:0305-1846
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Neuropathology And Applied Neurobiology. - 49 : 1 (2023), p. 1-4. -
További szerzők:Williamson, David Owen, Dylan M. Hortobágyi Tibor (1965-) (patológus) Troakes, Claire Aarsland, Dag
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7.

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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8.

001-es BibID:BIBFORM082383
035-os BibID:(cikkazonosító)551
Első szerző:Kattuah, Wejdan
Cím:Heterogeneous Nuclear Ribonucleoprotein E2 (hnRNP E2) Is a Component of TDP-43 Aggregates Specifically in the A and C Pathological Subtypes of Frontotemporal Lobar Degeneration / Wejdan Kattuah, Boris Rogelj, Andrew King, Christopher E. Shaw, Tibor Hortobágyi, Claire Troakes
Dátum:2019
ISSN:1662-453X
Megjegyzések:TAR DNA-binding protein 43 (TDP-43) is the major component of the ubiquitin-positive protein aggregates seen in the majority of frontotemporal lobar degeneration and amyotrophic lateral sclerosis cases. TDP-43 belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family that is involved in the regulation of RNA transcription, splicing, transport and translation. There are a great many hnRNPs, which often have overlapping functions and act cooperatively in RNA processing. Here we demonstrate that another hnRNP family member, hnRNP E2, shows a striking accumulation within dystrophic neurites and cytoplasmic inclusions in the frontal cortex and hippocampus of a subset of FTLD-TDP cases belonging to pathological subtypes A and C, where hnRNP E2 was found to co-localize with 87% of TDP-43 immunopositive inclusions. hnRNP E2-positive inclusions were not seen in FTLD-TDP cases with the C9orf72 expansion or in any other neurodegenerative disorders examined. This interaction with TDP-43 in specific FTLD subtypes suggests different underlying neurodegenerative pathways.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Frontiers in Neuroscience. - 13 (2019), p. 1-11. -
További szerzők:Rogelj, Boris King, Andrew Shaw, Christopher E. Hortobágyi Tibor (1965-) (patológus) Troakes, Claire
Pályázati támogatás:2017-1.2.1-NKP-2017-00002
Egyéb
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9.

001-es BibID:BIBFORM051639
035-os BibID:PMID: 22471883
Első szerző:Kovács G. Gábor
Cím:Neuropathology of the hippocampus in FTLD-Tau with Pick bodies : a study of the BrainNet Europe Consortium / G. G. Kovacs, A. J. M. Rozemuller, J. C. van Swieten, E. Gelpi, K. Majtenyi, S. Al-Sarraj, C. Troakes, I. Bódi, A. King, T. Hortobágyi, M. M. Esiri, O. Ansorge, G. Giaccone, I. Ferrer, T. Arzberger, N. Bogdanovic, T. Nilsson, I. Leisser, I. Alafuzoff, J. W. Ironside, H. Kretzschmar, H. Budka
Dátum:2013
ISSN:0305-1846
Megjegyzések:Aims: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurons. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. Methods: We evaluated immunoreactivity for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. Results: Mean age at death was 68.2 years (range 49 to 96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of FTD, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein immunoreactivity was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurons. Aβ immunoreactivity was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. Conclusions: 1) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; 2) even minor deviation from these morphological criteria suggests a different disorder; and 3) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.
Tárgyszavak:Orvostudományok Klinikai orvostudományok magyar nyelvű folyóiratközlemény hazai lapban
Megjelenés:Neuropathology and Applied Neurobiology. - 39 : 2 (2013), p. 166-178. -
További szerzők:Rozemuller, A. J. M. Swieten, John C. van Gelpi, Ellen Majtényi Katalin Al-Sarraj, Safa Troakes, Claire Bódi István (1967-) (neuropatológus) King, Andrew Hortobágyi Tibor (1965-) (patológus) Esiri, M. M. Ansorge, Olaf Giaccone, Giorgio Ferrer, Isidro Arzberger, Thomas Bogdanovic, Nenad Nilsson, Tatjana Leisser, I. Alafuzoff, Irina Ironside, James W. Kretzschmar, Hans Budka, Herbert
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10.

001-es BibID:BIBFORM063347
Első szerző:Niblock, Michael
Cím:Lack of association between TDP-43 pathology and tau mis-splicing in Alzheimer's disease / Michael Niblock, Tibor Hortobágyi, Claire Troakes, Safa Al-Sarraj, Carl Spickett, Rebecca Jones, Christopher E. Shaw, Jean-Marc Gallo
Dátum:2016
ISSN:0197-4580
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Neurobiology Of Aging 37 (2016), p. 45-46. -
További szerzők:Hortobágyi Tibor (1965-) (patológus) Troakes, Claire Al-Sarraj, Safa Spickett, Carl Jones, Rebecca Shaw, Christopher E. Gallo, Jean-Marc
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11.

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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12.

001-es BibID:BIBFORM063679
Első szerző:Peters, Owen M.
Cím:Gamma-synuclein pathology in amyotrophic lateral sclerosis / Owen M. Peters, Tatyana Shelkovnikova, John Robin Highley, Johnathan Cooper-Knock, Tibor Hortobagyi, Claire Troakes, Natalia Ninkina1, Vladimir L. Buchman
Dátum:2015
ISSN:2328-9503
Megjegyzések:sclerosis (ALS) is the presence of intracellular inclusions in degenerating neuronsand their axons. The appearance and localization of these pathologicalstructures depend on an aggregated protein that forms their scaffold. We investigatedif c-synuclein, an aggregation-prone protein highly expressed in healthymotor neurons, and predominantly localized in their axons and synaptic terminalsis involved in ALS pathology. Methods: Immunostaining of histologicalsections and sequential protein extraction from postmortem neural samplesfollowed by immunoblotting. Results: Immunohistochemical screening revealeda subset of sporadic (9 of 31) and familial (8 of 23) ALS cases with a novel typeof pathology characterized by the accumulation of c-synuclein in distinctprofiles within the dorsolateral column. Sequential fractionation of proteinsfrom the spinal cord tissues revealed detergent-insoluble c-synuclein speciesspecifically in the dorsolateral corticospinal tracts of a ALS patient withc-synuclein-positive profiles in this region. These profiles are negative for proteinmarkers commonly found in pathological inclusions in the spinal cord ofALS patients and most probably represent degenerated axons of upper motorneurons that have lost their neurofilaments. A subset of these profiles wasfound in association with phagocytic cells positive for Mac-2/Galectin-3. Asmaller subset of studied ALS cases (4 of 54) contained large cytoplasmic inclusionsin the cell body of remaining spinal motor neurons. Interpretation: Ourobservations suggest that pathological aggregation of c-synuclein might contributeto the pathogenesis of ALS.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Annals of Clinical and Translational Neurology. - 2 : 1 (2015), p. 29-37. -
További szerzők:Shelkovnikova, Tatyana Highley, John Robin Cooper-Knock, Johnathan Hortobágyi Tibor (1965-) (patológus) Troakes, Claire Ninkina, Natalia Buchman, Vladimir L.
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