Small molecule 1a reduces FMRpolyG-mediated toxicity in in vitro and in vivo models for FMR1 premutation.
Small molecule 1a reduces FMRpolyG-mediated toxicity in in vitro and in vivo models for FMR1 premutation.
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小分子1a降低了FMRPolyg介导的fMR1前体体体内和体内模型中的毒性。
DOI：
10.1093/hmg/ddab143
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发表时间：
2021-08-12
影响因子：
3.5
通讯作者：
Hukema RK
中科院分区：
文献类型：
--
作者：
Haify SN;Buijsen RAM;Verwegen L;Severijnen LWFM;de Boer H;Boumeester V;Monshouwer R;Yang WY;Cameron MD;Willemsen R;Disney MD;Hukema RK
脆性X相关震颤和共济失调综合征（FXTAS）是一种迟发性、进行性神经退行性疾病，其特征在于震颤、共济失调和神经心理问题。这种疾病在一般人群中相当常见，全世界约有2000万携带者。患FXTAS的风险随着年龄的增长而急剧增加，大约45%的50岁以上的男性携带者受到影响。FXTAS是由脆性X智力低下1（FMR 1）基因中的CGG重复扩增（CGGexp）引起的。CGGexp RNA通过称为RAN翻译的机制翻译成FMRpolyG蛋白。虽然基因和致病触发因素都是已知的，但目前还没有治疗干预措施。在这里，我们提出，第一次，主要海马神经元来自无处不在的诱导型小鼠模型，这是作为一个筛选工具，有针对性的干预措施。一个有前途的候选者是重复结合，RAN翻译阻断，小分子1a。小分子1a保护致病CGGexp不被翻译成有毒的FMRpolyG蛋白。原代海马神经元形成FMRpolyG阳性包涵体，并且在用1a处理后，FMRpolyG阳性包涵体的数量减少。我们还首次描述了该小鼠模型肝脏中FMRpolyG阳性包涵体的形成。用1a处理减少了肝脏中的不溶性FMRpolyG蛋白部分，但没有减少包涵体的数量。此外，1a处理对Rad23b阳性内含物的数量和不溶性Rad23b蛋白水平具有降低作用。这些数据表明，靶向小分子疗法在FXTAS小鼠模型中有效，并有可能治疗CGGexp介导的疾病，包括FXTAS。
Fragile X-associated tremor and ataxia syndrome (FXTAS) is a late-onset, progressive neurodegenerative disorder characterized by tremors, ataxia and neuropsychological problems. This disease is quite common in the general population with approximately 20 million carriers worldwide. The risk of developing FXTAS increases dramatically with age, with about 45% of male carriers over the age of 50 being affected. FXTAS is caused by a CGG-repeat expansion (CGGexp) in the fragile X mental retardation 1 (FMR1) gene. CGGexp RNA is translated into the FMRpolyG protein by a mechanism called RAN translation. Although both gene and pathogenic trigger are known, no therapeutic interventions are available at this moment. Here, we present, for the first time, primary hippocampal neurons derived from the ubiquitous inducible mouse model which is used as a screening tool for targeted interventions. A promising candidate is the repeat binding, RAN translation blocking, small molecule 1a. Small molecule 1a shields the disease-causing CGGexp from being translated into the toxic FMRpolyG protein. Primary hippocampal neurons formed FMRpolyG-positive inclusions, and upon treatment with 1a, the numbers of FMRpolyG-positive inclusions are reduced. We also describe for the first time the formation of FMRpolyG-positive inclusions in the liver of this mouse model. Treatment with 1a reduced the insoluble FMRpolyG protein fraction in the liver but not the number of inclusions. Moreover, 1a treatment had a reducing effect on the number of Rad23b-positive inclusions and insoluble Rad23b protein levels. These data suggest that targeted small molecule therapy is effective in an FXTAS mouse model and has the potential to treat CGGexp-mediated diseases, including FXTAS.
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影响因子：
4
作者：
Disney, Matthew D.;Liu, Biao;Childs-Disney, Jessica L.
通讯作者：
Childs-Disney, Jessica L.
影响因子：
3.5
作者：
Hashem, Vera;Galloway, Jocelyn N.;Nelson, David L.
通讯作者：
Nelson, David L.
影响因子：
2.3
作者：
Gokden, Murat;Al-Hinti, Jomana T.;Harik, Sami I.
通讯作者：
Harik, Sami I.
DOI：
10.1146/annurev-pharmtox-010715-103910
发表时间：
2016
影响因子：
12.5
作者：
Childs-Disney JL;Disney MD
通讯作者：
Disney MD
影响因子：
12.7
作者：
Hunsaker MR;Greco CM;Spath MA;Smits AP;Navarro CS;Tassone F;Kros JM;Severijnen LA;Berry-Kravis EM;Berman RF;Hagerman PJ;Willemsen R;Hagerman RJ;Hukema RK
通讯作者：
Hukema RK