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

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• 作者：Silvia Olivera-Bravo^a ; Luis Barbeito^b ; ^{barbeito@pasteur.edu.uy" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Astrocyte dysfunction ; Glutaric acidemia I ; Neuronal death ; Defective myelination
• 刊名：FEBS Letters
• 出版年：2015
• 出版时间：14 November 2015
• 年：2015
• 卷：589
• 期：22
• 页码：3492-3497
• 全文大小：848 K

文摘

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.