Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases.
Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases.
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DOI：
10.1016/j.neuron.2021.03.038
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发表时间：
2021-06-02
期刊：
影响因子：
16.2
通讯作者：
Charlet-Berguerand N
中科院分区：
文献类型：
--
作者：
Boivin M;Deng J;Pfister V;Grandgirard E;Oulad-Abdelghani M;Morlet B;Ruffenach F;Negroni L;Koebel P;Jacob H;Riet F;Dijkstra AA;McFadden K;Clayton WA;Hong D;Miyahara H;Iwasaki Y;Sone J;Wang Z;Charlet-Berguerand N
神经元核内包涵体病(NIID)是一种以来源不明的核内包涵体的存在为特征的神经退行性疾病。NIID是由NOTCH2NLC(N2C)基因5‘非编码区GGC重复序列的扩增引起的。我们发现这些重复序列嵌入到一个小的上游开放阅读框架(UORF)(UN2C)中，导致它们翻译成含有多甘氨酸的蛋白质uN2CPolyG。这种蛋白在细胞和小鼠模型中的核内包涵体中积累，在NIID患者的组织样本中积累。此外，uN2CPolyG在小鼠体内的表达会导致动物的运动改变、神经细胞丢失和过早死亡。这些结果表明，扩展的GGC重复序列翻译成一种新的致病多甘氨酸蛋白是NIID核内包涵体和神经变性存在的基础。NIID是一种由NOTCH2NLC中GGC重复序列的扩张引起的神经退行性疾病，这些GGC重复序列被翻译成一种多甘氨酸(PolyG)蛋白，PolyG蛋白具有毒性，在细胞和动物中形成核内包涵体。FXTAS和NIID的相似性定义了一组新的疾病：PolyG疾病神经退行性疾病NIID是由NOTCH2NLC中GGC重复序列的扩张引起的。Boivin等人。发现这些重复序列被翻译成一种有毒的聚甘氨酸(PolyG)蛋白，形成核内包涵体。FXTAS中存在相同的机制，揭示了一组新的遗传病理--多发性G病。
Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by the presence of intranuclear inclusions of unknown origin. NIID is caused by an expansion of GGC repeats in the 5′ UTR of the NOTCH2NLC (N2C) gene. We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG. This protein accumulates in intranuclear inclusions in cell and mouse models and in tissue samples of individuals with NIID. Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals. These results suggest that translation of expanded GGC repeats into a novel and pathogenic polyglycine-containing protein underlies the presence of intranuclear inclusions and neurodegeneration in NIID. NIID is a neurodegenerative disease caused by expansion of GGC repeats in NOTCH2NLC These GGC repeats are translated into a polyglycine (polyG) protein The polyG protein is toxic and forms intranuclear inclusions in cells and animals Similarities between FXTAS and NIID define a new set of disorders: polyG diseases The neurodegenerative disease NIID is caused by an expansion of GGC repeats in NOTCH2NLC. Boivin et al. found that these repeats are translated into a toxic polyglycine (polyG) protein that forms intranuclear inclusions. An identical mechanism exists in FXTAS, unveiling a novel group of genetic pathologies, the polyG diseases.
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影响因子：
9.9
作者：
MUNOZGARCIA, D;LUDWIN, SK
通讯作者：
LUDWIN, SK
重新定义神经元核内包涵体病的临床病理学谱。
影响因子：
5.3
作者：
Chen H;Lu L;Wang B;Cui G;Wang X;Wang Y;Raza HK;Min Y;Li K;Cui Y;Miao Z;Wan B;Sun M;Xu X
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Xu X
影响因子：
3.4
作者：
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通讯作者：
Bochicchio, Brigida
影响因子：
7.1
作者：
Ogasawara M;Iida A;Kumutpongpanich T;Ozaki A;Oya Y;Konishi H;Nakamura A;Abe R;Takai H;Hanajima R;Doi H;Tanaka F;Nakamura H;Nonaka I;Wang Z;Hayashi S;Noguchi S;Nishino I
通讯作者：
Nishino I
影响因子：
64.5
作者：
Fiddes IT;Lodewijk GA;Mooring M;Bosworth CM;Ewing AD;Mantalas GL;Novak AM;van den Bout A;Bishara A;Rosenkrantz JL;Lorig-Roach R;Field AR;Haeussler M;Russo L;Bhaduri A;Nowakowski TJ;Pollen AA;Dougherty ML;Nuttle X;Addor MC;Zwolinski S;Katzman S;Kriegstein A;Eichler EE;Salama SR;Jacobs FMJ;Haussler D
通讯作者：
Haussler D