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001-es BibID:	BIBFORM082379
035-os BibID:	(cikkazonosító)2909168
Első szerző:	Babić Leko, Mirjana
Cím:	Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion / Mirjana Babić Leko, Vera Župunski, Jason Kirincich, Dinko Smilović, Tibor Hortobágyi, Patrick R. Hof, Goran Šimić
Dátum:	2019
ISSN:	0953-4180
Megjegyzések:	Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2-10 hexanucleotide GGGGCC repeats in the C9orf72 gene, while more than a few hundred repeats represent a risk for ALS and FTD. The proposed molecular mechanisms by which C9orf72 repeat expansions induce neurodegenerative changes are C9orf72 loss-of-function through haploinsufficiency, RNA toxic gain-of-function, and gain-of-function through the accumulation of toxic dipeptide repeat proteins. However, many more cellular processes are affected by pathological processes in C9FTD/ALS, including nucleocytoplasmic transport, RNA processing, normal function of nucleolus, formation of membraneless organelles, translation, ubiquitin proteasome system, Notch signalling pathway, granule transport, and normal function of TAR DNA-binding protein 43 (TDP-43). Although the exact molecular mechanisms through which C9orf72 repeat expansions account for neurodegeneration have not been elucidated, some potential therapeutics, such as antisense oligonucleotides targeting hexanucleotide GGGGCC repeats in mRNA, were successful in preclinical trials and are awaiting phase 1 clinical trials. In this review, we critically discuss each proposed mechanism and provide insight into the most recent studies aiming to elucidate the molecular underpinnings of C9FTD/ALS.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Behavioural Neurology. - 2019 (2019), p. 1-18. -
További szerzők:	Župunski, Vera Kirincich, Jason Smilović, Dinko Hortobágyi Tibor (1965-) (patológus) Hof, Patrick R. Šimić, Goran
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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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
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat Szerző által megadott URL DOI
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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
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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