Growth Differentiation Factor 15 Elevation in the Central Nervous System Is Associated With Failure to Thrive in Alexander Disease

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OBJECTIVE: Alexander disease (AxD) is a severe neurodegenerative disorder caused by gain-of-function mutations in the gene for GFAP, which lead to protein aggregation and a primary astrocytopathy. Symptoms vary, but failure to thrive (FTT) and frequent emesis are common and cause significant morbidity. Here we investigate GDF15, a member of the TGFβ superfamily, which regulates energy balance and appetite, as a potential mediator of FTT in AxD. METHODS: rat model (R237H), in which pups fail to gain weight after weaning and become frail and impaired as they mature, to assess muscle atrophy, energy expenditure, and feeding behavior in AxD. We measure GDF15 in brain and cerebrospinal fluid (CSF), assess activation of its receptor GFRAL in area postrema neurons, and use GFAP suppression to correlate FTT phenotypes with GDF15 expression. Finally, we measure GDF15 in patients with AxD. RESULTS: R237H rats show reduced lean and fat mass and muscle atrophy despite reduced energy expenditure, and at an early age exhibit pica and anorexia. GDF15 is expressed by R237H rat astrocytes and is elevated in brainstem and CSF, but not in plasma. Neurons expressing GFRAL, a mediator of GDF15-induced appetite suppression, are activated in the area postrema. Suppression of GFAP using antisense oligonucleotides normalizes weight gain and GDF15 levels in brainstem and CSF. In human AxD, GDF15 is elevated in CSF, but not in blood. INTERPRETATION: GDF15 is associated with FTT in AxD and provides both a target and useful biomarker for the development of future therapeutics.

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