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Karyopherin abnormalities in neurodegenerative proteinopathies.
Pasha, Terouz; Zatorska, Anna; Sharipov, Daulet; Rogelj, Boris; Hortobágyi, Tibor; Hirth, Frank.
  • Pasha T; King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London SE5 9RT, UK.
  • Zatorska A; King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London SE5 9RT, UK.
  • Sharipov D; King's College London, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, London SE5 9RT, UK.
  • Rogelj B; Jozef Stefan Institute, Department of Biotechnology, 1000 Ljubljana, Slovenia.
  • Hortobágyi T; University of Ljubljana, Faculty of Chemistry and Chemical Technology, 1000 Ljubljana, Slovenia.
  • Hirth F; ELKH-DE Cerebrovascular and Neurodegenerative Research Group, Department of Neurology, University of Debrecen, 4032 Debrecen, Hungary.
Brain ; 144(10): 2915-2932, 2021 11 29.
Article in English | MEDLINE | ID: covidwho-1238183
ABSTRACT
Neurodegenerative proteinopathies are characterized by progressive cell loss that is preceded by the mislocalization and aberrant accumulation of proteins prone to aggregation. Despite their different physiological functions, disease-related proteins like tau, α-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-mislocalized aggregates that characterize the stages and severity of neurodegenerative diseases. Recent advances into the underlying pathogenic mechanisms have associated mislocalization 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 mislocalization and aggregation of karyopherin α and ß 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 mislocalization 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Neurodegenerative Diseases / Karyopherins / Proteostasis Deficiencies Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Brain Year: 2021 Document Type: Article Affiliation country: Brain

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Neurodegenerative Diseases / Karyopherins / Proteostasis Deficiencies Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Brain Year: 2021 Document Type: Article Affiliation country: Brain