title: A role for astrocytes in cerebellar deficits in frataxin deficiency: Protection by insulin-like growth factor I.
abstract: 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.
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain; CIBERNED, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Franco
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain; CIBERNED, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Genis
authors.affiliation: Regensburg University, Regensburg, Germany.
authors.forename: J A
authors.initials: JA
authors.lastname: Navarro
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain; CIBERNED, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Perez-Domper
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain; CIBERNED, Spain.
authors.forename: A M
authors.initials: AM
authors.lastname: Fernandez
authors.affiliation: Regensburg University, Regensburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schneuwly
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain; CIBERNED, Spain. Electronic address: torres@cajal.csic.es.
authors.forename: I
authors.initials: I
authors.lastname: Torres Alemán
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology*; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D064026:Calbindins / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology*; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005621:Friedreich Ataxia / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000627:therapeutic use*; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology; D011596:Psychomotor Disorders / Q000209:etiology / Q000517:prevention & control; D017382:Reactive Oxygen Species / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D000096923:Frataxin
chemical_list: D064026:Calbindins; D029721:Drosophila Proteins; D005904:Glial Fibrillary Acidic Protein; D007334:Insulin-Like Growth Factor I; D033862:Iron-Binding Proteins; D010751:Phosphopyruvate Hydratase; D017382:Reactive Oxygen Species; D017526:Receptor, IGF Type 1; D000096923:Frataxin
keywords: Astrocytes; Brain development; Frataxin deficiency; Insulin-like growth factor I