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001-es BibID:	BIBFORM095314
035-os BibID:	(WoS)000733375400006 (Scopus)85113789602
Első szerző:	Pasha, Terouz
Cím:	Karyopherin abnormalities in neurodegenerative proteinopathies / Terouz Pasha, Anna Zatorska, Daulet Sharipov, Boris Rogelj, Tibor Hortobágyi, Frank Hirth
Dátum:	2021
ISSN:	0006-8950
Megjegyzések:	Neurodegenerative proteinopathies are characterised by progressive cell loss that is preceded by the mislocalisation and aberrant accumulation of proteins prone to aggregation. Despite their different physiological functions, disease-related proteins like tau, alpha-synuclein, Tar DNA binding protein-43, Fused in sarcoma and mutant Huntingtin, all share low complexity regions that can mediate their liquid-liquid phase transitions. The proteins' phase transitions can range from native monomers to soluble oligomers, liquid droplets and further to irreversible, often-mislocalised aggregates that characterise the stages and severity of neurodegenerative diseases. Recent advances into the underlying pathogenic mechanisms have associated mislocalisation and aberrant accumulation of disease-related proteins with defective nucleocytoplasmic transport and its mediators called karyopherins. These studies identify karyopherin abnormalities in amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, and synucleinopathies including Parkinson's disease and dementia with Lewy bodies, that range from altered expression levels to the subcellular mislocalisation and aggregation of karyopherin alpha and beta proteins. The reported findings reveal that in addition to their classical function in nuclear import and export, karyopherins can also act as chaperones by shielding aggregation-prone proteins against misfolding, accumulation and irreversible phase-transition into insoluble aggregates. Karyopherin abnormalities can, therefore, be both the cause and consequence of protein mislocalisation and aggregate formation in degenerative proteinopathies. The resulting vicious feedback cycle of karyopherin pathology and proteinopathy identifies karyopherin abnormalities as a common denominator of onset and progression of neurodegenerative disease. Pharmacological targeting of karyopherins, already in clinical trials as therapeutic intervention targeting cancers such as glioblastoma and viral infections like COVID-19, may therefore represent a promising new avenue for disease-modifying treatments in neurodegenerative proteinopathies.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Brain. - 144 : 10 (2021), p. 2915-2932. -
További szerzők:	Zatorska, Anna Sharipov, Daulet Rogelj, Boris Hortobágyi Tibor (1965-) (patológus) Hirth, Frank
Pályázati támogatás:	Nemzeti Agykutatási Program 2017-1.2.1-NKP-2017-00002 Egyéb NKFIH-SNN-132999 Egyéb
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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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
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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