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

IF 3.9 2区 医学 Q1 CLINICAL NEUROLOGY
Tracy L Hagemann, Michelle M Sonsalla, Cora Luzinski, Fernando Zacahua, David A Harris, Dudley W Lamming, Albee Messing
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Abstract

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: In this study, we use the Gfap+/R237H 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.

生长分化因子15在中枢神经系统中的升高与亚历山大病的生长失败有关
目的:亚历山大病(AxD)是一种严重的神经退行性疾病,由GFAP基因的功能获得性突变引起,导致蛋白质聚集和原发性星形细胞病变。症状各不相同,但发育不全(FTT)和频繁呕吐是常见的,并导致显著的发病率。本文研究了调节能量平衡和食欲的TGFβ超家族成员GDF15作为AxD中FTT的潜在介质。方法:在本研究中,我们使用Gfap+/R237H大鼠模型(R237H)来评估AxD的肌肉萎缩、能量消耗和摄食行为。在Gfap+/R237H模型中,幼鼠在断奶后无法增加体重,并在成熟后变得虚弱和受损。我们测量了脑和脑脊液(CSF)中的GDF15,评估了其受体GFRAL在脑后神经元区域的激活情况,并利用GFAP抑制将FTT表型与GDF15表达联系起来。最后,我们测量了AxD患者的GDF15。结果:R237H大鼠尽管能量消耗减少,但瘦脂肪量减少,肌肉萎缩,幼年时出现异食癖和厌食。GDF15在R237H大鼠星形胶质细胞中表达,在脑干和脑脊液中表达升高,而在血浆中不表达。GFRAL是gdf15诱导食欲抑制的介质,表达GFRAL的神经元在脑后区域被激活。使用反义寡核苷酸抑制GFAP可使体重增加和脑干和脑脊液中GDF15水平正常化。在人类AxD中,GDF15在CSF中升高,但在血液中没有升高。解释:GDF15与AxD中的FTT相关,为未来治疗方法的开发提供了靶标和有用的生物标志物。
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来源期刊
Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)
CiteScore
9.10
自引率
1.90%
发文量
218
审稿时长
8 weeks
期刊介绍: Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.
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