A role for astrocytes in cerebellar deficits in frataxin deficiency: Protection by insulin-like growth factor I
| العنوان: | A role for astrocytes in cerebellar deficits in frataxin deficiency: Protection by insulin-like growth factor I |
|---|---|
| المؤلفون: | Agudo Fernández, JA Navarro, Laura Genís, I. Torres Aleman, Stephan Schneuwly, C Franco, Paloma Pérez-Domper |
| المساهمون: | Ministerio de Ciencia e Innovación (España) |
| المصدر: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| بيانات النشر: | Elsevier, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Calbindins, medicine.medical_treatment, Receptor, IGF Type 1, Insulin-like growth factor, Mice, 0302 clinical medicine, Cerebellum, Iron-Binding Proteins, Drosophila Proteins, Insulin-Like Growth Factor I, biology, Neurodegeneration, Insulin-like growth factor I, Brain development, Cerebellar atrophy, Drosophila, medicine.symptom, Stem cell, medicine.medical_specialty, Ataxia, Frataxin deficiency, 03 medical and health sciences, Cellular and Molecular Neuroscience, Prosencephalon, Internal medicine, Glial Fibrillary Acidic Protein, medicine, Animals, Humans, Molecular Biology, Growth factor, Body Weight, Cell Biology, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Endocrinology, Animals, Newborn, Friedreich Ataxia, Phosphopyruvate Hydratase, Astrocytes, Forebrain, Frataxin, biology.protein, Psychomotor Disorders, Reactive Oxygen Species, Neuroscience, 030217 neurology & neurosurgery |
| الوصف: | Inherited neurodegenerative diseases such as Friedreich's ataxia (FRDA), produced by deficiency of the mitochondrial chaperone frataxin (Fxn), shows specific neurological deficits involving different subset of neurons even though deficiency of Fxn is ubiquitous. Because astrocytes are involved in neurodegeneration, we analyzed whether they are also affected by frataxin deficiency and contribute to the disease. We also tested whether insulin-like growth factor I (IGF-I), that has proven effective in increasing frataxin levels both in neurons and in astrocytes, also exerts in vivo protective actions. Using the GFAP promoter expressed by multipotential stem cells during development and mostly by astrocytes in the adult, we ablated Fxn in a time-dependent manner in mice (FGKO mice) and found severe ataxia and early death when Fxn was eliminated during development, but not when deleted in the adult. Analysis of underlying mechanisms revealed that Fxn deficiency elicited growth and survival impairments in developing cerebellar astrocytes, whereas forebrain astrocytes grew normally. A similar time-dependent effect of frataxin deficiency in astrocytes was observed in a fly model. In addition, treatment of FGKO mice with IGF-I improved their motor performance, reduced cerebellar atrophy, and increased survival. These observations indicate that a greater vulnerability of developing cerebellar astrocytes to Fxn deficiency may contribute to cerebellar deficits in this inherited disease. Our data also confirm a therapeutic benefit of IGF-I in early FRDA deficiency. This work was supported by Spanish Ministry of Science (SAF2010–60051/SAF2013–40710-R), by CIBERNED, and by the Elitenetzwerk Bayern. |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f7572f2939945c63d8c3b53ab715fc85 http://hdl.handle.net/10261/200268 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....f7572f2939945c63d8c3b53ab715fc85 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |