A role for astrocytes in cerebellar deficits in frataxin deficiency: Protection by insulin-like growth factor I
| Autor: | Agudo Fernández, JA Navarro, Laura Genís, I. Torres Aleman, Stephan Schneuwly, C Franco, Paloma Pérez-Domper |
|---|---|
| Přispěvatelé: | Ministerio de Ciencia e Innovación (España) |
| Rok vydání: | 2017 |
| Předmět: |
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 |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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