The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity
| العنوان: | The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity |
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| المؤلفون: | Samuel J. Seguin, Angelo Poletti, Valeria Crippa, Nandini Ramesh, Elena Zelotti, Serena Carra, Jenna M. Gregory, Udai Bhan Pandey, Ilaria Bigi, Madina Baratashvili, Christopher M. Dobson, Massimo Ganassi, Maria Elena Cicardi, Chiara Diacci, Cristina Cereda |
| المصدر: | Human Molecular Genetics Human Molecular Genetics, 25(18), 3908-3924. Oxford University Press Crippa, V, Cicardi, M E, Ramesh, N, Seguin, S J, Ganassi, M, Bigi, I, Diacci, C, Zelotti, E, Baratashvili, M, Gregory, J M, Dobson, C M, Cereda, C, Pandey, U B, Poletti, A & Carra, S 2016, ' The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity ', Human Molecular Genetics, vol. 25, no. 18, pp. 3908-3924 . https://doi.org/10.1093/hmg/ddw232Test |
| بيانات النشر: | Oxford University Press (OUP), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Protein aggregation, Eye, AMYOTROPHIC-LATERAL-SCLEROSIS, Mice, 0302 clinical medicine, AUTOPHAGIC REMOVAL, POLYGLUTAMINE TRACT, Molecular Biology, Genetics, Genetics (clinical), Drosophila Proteins, Heat-Shock Proteins, Motor Neurons, biology, Neurodegeneration, Pupa, Articles, General Medicine, Cell biology, DNA-Binding Proteins, Drosophila melanogaster, BULBAR MUSCULAR-ATROPHY, MOTOR-NEURON DISEASES, Transgene, Mice, Transgenic, Protein Serine-Threonine Kinases, Protein Aggregation, Pathological, 03 medical and health sciences, Downregulation and upregulation, Heat shock protein, mental disorders, medicine, Animals, Humans, FRONTOTEMPORAL LOBAR DEGENERATION, MUTANT ANDROGEN RECEPTOR, Amyotrophic Lateral Sclerosis, nutritional and metabolic diseases, medicine.disease, biology.organism_classification, Molecular biology, Peptide Fragments, nervous system diseases, Tissue Degeneration, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, Chaperone (protein), biology.protein, NEURODEGENERATIVE DISEASES, 030217 neurology & neurosurgery, MISFOLDED PROTEINS, Molecular Chaperones |
| الوصف: | Aggregation of TAR-DNA-binding protein 43 (TDP-43) and of its fragments TDP-25 and TDP-35 occurs in amyotrophic lateral sclerosis (ALS). TDP-25 and TDP-35 act as seeds for TDP-43 aggregation, altering its function and exerting toxicity. Thus, inhibition of TDP-25 and TDP-35 aggregation and promotion of their degradation may protect against cellular damage. Upregulation of HSPB8 is one possible approach for this purpose, since this chaperone promotes the clearance of an ALS associated fragments of TDP-43 and is upregulated in the surviving motor neurones of transgenic ALS mice and human patients. We report that overexpression of HSPB8 in immortalized motor neurones decreased the accumulation of TDP-25 and TDP-35 and that protection against mislocalized/truncated TDP-43 was observed for HSPB8 in Drosophila melanogaster. Overexpression of HSP67Bc, the functional ortholog of human HSPB8, suppressed the eye degeneration caused by the cytoplasmic accumulation of a TDP-43 variant with a mutation in the nuclear localization signal (TDP-43-NLS). TDP-43-NLS accumulation in retinal cells was counteracted by HSP67Bc overexpression. According with this finding, downregulation of HSP67Bc increased eye degeneration, an effect that is consistent with the accumulation of high molecular weight TDP-43 species and ubiquitinated proteins. Moreover, we report a novel Drosophila model expressing TDP-35, and show that while TDP-43 and TDP-25 expression in the fly eyes causes a mild degeneration, TDP-35 expression leads to severe neurodegeneration as revealed by pupae lethality; the latter effect could be rescued by HSP67Bc overexpression. Collectively, our data demonstrate that HSPB8 upregulation mitigates TDP-43 fragment mediated toxicity, in mammalian neuronal cells and flies. |
| وصف الملف: | application/pdf |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7f35b9b239d082ddb60756ff8e436c92Test https://doi.org/10.1093/hmg/ddw232Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7f35b9b239d082ddb60756ff8e436c92 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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