A role of astrocytes in mediating postnatal neurodegeneration in Glutaric acidemia-type 1

Astrocytes are crucial for postnatal development of neuronal networks, axon myelination and neurovascular structures. Defects in astrocyte generation or maturation are associated with severe neurological developmental disorders. Glutaric acidemia type I (GAI), an inherited neurometabolic disorder ch...

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Bibliographic Details
Published in:FEBS letters 2015-11, Vol.589 (22), p.3492-3497
Main Authors: Olivera-Bravo, Silvia, Barbeito, Luis
Format: Article
Language:English
Subjects:
Amino Acid Metabolism, Inborn Errors - metabolism
Amino Acid Metabolism, Inborn Errors - pathology
Amino Acid Metabolism, Inborn Errors - therapy
Animals
Astrocyte dysfunction
Astrocytes - metabolism
Astrocytes - pathology
Brain Diseases, Metabolic - metabolism
Brain Diseases, Metabolic - pathology
Brain Diseases, Metabolic - therapy
Defective myelination
Glutarates - metabolism
Glutaric acidemia I
Glutaryl-CoA Dehydrogenase - deficiency
Glutaryl-CoA Dehydrogenase - metabolism
Humans
Neuronal death
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Summary:Astrocytes are crucial for postnatal development of neuronal networks, axon myelination and neurovascular structures. Defects in astrocyte generation or maturation are associated with severe neurological developmental disorders. Glutaric acidemia type I (GAI), an inherited neurometabolic disorder characterized by accumulation of glutaric (GA) and 3-hydroxyglutaric acids, shows a paradigmatic postnatal neuropathology characterized by massive degeneration of neurons in the striatum. While the disorder is caused by genetic mutations on glutaryl-CoA dehydrogenase, the neurological defects usually start months after birth. Pathogenesis of GAI has remained largely unknown, and specifically, it is unclear how accumulation of GAI metabolites may result in neurodegeneration. Recent evidence supports a GAI model involving primary defective astrocyte maturation leading to a co-morbid spectrum of neurologic symptoms similar to those of patients. Astrocytes are vulnerable to GAI metabolites, but instead of dying, they follow long-lasting phenotypic changes leading to striatal neuron degeneration as well as defective myelination and blood brain barrier maturation. Here, we summarized recent findings on the pathogenic role of GA-damaged astrocytes in GAI and discuss if astrocyte dysfunction may be a target of therapeutic interventions.
ISSN:0014-5793
1873-3468
DOI:10.1016/j.febslet.2015.09.010