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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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001-es BibID:	BIBFORM020036
Első szerző:	Maekawa, Satomi
Cím:	TDP-43 is consistently co-localized with ubiquitinated inclusions in sporadic and Guam amyotrophic lateral sclerosis but not in familial amyotrophic lateral sclerosis with and without SOD1 mutations / Satomi Maekawa, P. Nigel Leigh, Andrew King, Edith Jones, John C. Steele, Istvan Bodi, Christopher E. Shaw, Tibor Hortobagyi, Safa Al-Sarraj
Dátum:	2009
ISSN:	0919-6544
Megjegyzések:	The transactive response (TAR) DNA binding protein 43 (TDP-43) has been recently implicated as a major component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS, motor neuron disease: MND) and ALS-related disorders. In this study, we examined abnormal TDP-43 pathology in 13 sporadic ALS (SALS), six familial ALS (FALS) with and without Cu/Zn superoxide dismutase (SOD1) mutations (SOD1-FALS and non-SOD1-FALS), Guam ALS, two frontotemporal lobar degeneration with MND/ALS (FTLD-MND/ALS), one FTLD with ubiquitin-only-immunoreactive inclusions (FTLD-U) and two progressive supranuclear palsy (PSP). Sections from the spinal cord were processed for immunohistochemistry using antibodies against TDP-43, ubiquitin, p62, cystatin C, phosphorylated tau protein (P-tau; AT8), alpha-synuclein and phosphorylated neurofilament protein (P-NF). In 12 out of 13 SALS and both Guam ALS cases ubiquitin and p62-immunoreactive (IR) neuronal inclusions co-localized with TDP-43. In three out of four SOD1-FALS and one of two non-SOD1-FALS cases, TDP-43-IR inclusions were absent despite the presence of p62 and/or ubiquitin-IR inclusions. However, a single TDP-43-IR neuronal inclusion co-localized with p62 and ubiquitin in one SOD1-FALS (His48Gln) case. Except for one neuron in a Guam case, all TDP-43-IR neuronal inclusions were negative for P-tau (AT8). TDP-43-IR glial inclusions and neurites were also demonstrated. The TDP-43 is a consistent component of the ubiquitinated inclusions in SALS and Guam ALS, but TDP-43-IR inclusions are absent or scarce in SOD1-FALS.
Tárgyszavak:	Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Neuropathology. - 29 : 6 (2009), p. 672-683. -
További szerzők:	Leigh, P. Nigel King, Andrew Jones, Edith Steele, John C. Bódi István (1967-) (neuropatológus) Shaw, Christopher E. Hortobágyi Tibor (1965-) (patológus) Al-Sarraj, Safa
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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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