Interferon beta induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice
| العنوان: | Interferon beta induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice |
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| المؤلفون: | Annie Sittler, Sandro Alves, Alexis Brice, Martine Barkats, Béatrice Dufresnois, Jean-Gabriel Dornbierer, Alexandre Janer, Christelle Tesson, Darren P. Baker, Morwena Latouche, Merle Ruberg, Martina Marinello, Giovanni Stevanin, Khalid Hamid El Hachimi, Alice Chort |
| المصدر: | Brain. 136:1732-1745 |
| بيانات النشر: | Oxford University Press (OUP), 2013. |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Adult, Cerebellum, Pathology, medicine.medical_specialty, Ataxin 7, Purkinje cell, Mice, Transgenic, Nerve Tissue Proteins, Motor Activity, Mice, Promyelocytic leukemia protein, Gene knockin, medicine, Animals, Humans, Spinocerebellar Ataxias, Gene Knock-In Techniques, Rats, Wistar, Child, Receptor, Cells, Cultured, Aged, Ataxin-7, biology, Interferon-beta, medicine.disease, Rats, Cell biology, Mice, Inbred C57BL, medicine.anatomical_structure, Ataxin, Mutation, Spinocerebellar ataxia, biology.protein, Neurology (clinical) |
| الوصف: | We showed previously, in a cell model of spinocerebellar ataxia 7, that interferon beta induces the expression of PML protein and the formation of PML protein nuclear bodies that degrade mutant ataxin 7, suggesting that the cytokine, used to treat multiple sclerosis, might have therapeutic value in spinocerebellar ataxia 7. We now show that interferon beta also induces PML-dependent clearance of ataxin 7 in a preclinical model, SCA7(266Q/5Q) knock-in mice, and improves motor function. Interestingly, the presence of mutant ataxin 7 in the mice induces itself the expression of endogenous interferon beta and its receptor. Immunohistological studies in brains from two patients with spinocerebellar ataxia 7 confirmed that these modifications are also caused by the disease in humans. Interferon beta, administered intraperitoneally three times a week in the knock-in mice, was internalized with its receptor in Purkinje and other cells and translocated to the nucleus. The treatment induced PML protein expression and the formation of PML protein nuclear bodies and decreased mutant ataxin 7 in neuronal intranuclear inclusions, the hallmark of the disease. No reactive gliosis or other signs of toxicity were observed in the brain or internal organs. The performance of the SCA7(266Q/5Q) knock-in mice was significantly improved on two behavioural tests sensitive to cerebellar function: the Locotronic® Test of locomotor function and the Beam Walking Test of balance, motor coordination and fine movements, which are affected in patients with spinocerebellar ataxia 7. In addition to motor dysfunction, SCA7(266Q/5Q) mice present abnormalities in the retina as in patients: ataxin 7-positive neuronal intranuclear inclusions that were reduced by interferon beta treatment. Finally, since neuronal death does not occur in the cerebellum of SCA7(266Q/5Q) mice, we showed in primary cell cultures expressing mutant ataxin 7 that interferon beta treatment improves Purkinje cell survival. |
| تدمد: | 1460-2156 0006-8950 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3b9c34d96ef6d3b3cdd44c3bb260df1dTest https://doi.org/10.1093/brain/awt061Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3b9c34d96ef6d3b3cdd44c3bb260df1d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602156 00068950 |
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