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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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