首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >CNS expression of glucocerebrosidase corrects α-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy
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CNS expression of glucocerebrosidase corrects α-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy

机译:葡萄糖脑苷脂酶的中枢神经系统表达纠正高雪相关突触核蛋白病小鼠模型中的α-突触核蛋白病理学和记忆

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摘要

Emerging genetic and clinical evidence suggests a link between Gaucher disease and the synucleinopathies Parkinson disease and dementia with Lewy bodies. Here, we provide evidence that a mouse model of Gaucher disease (Gba1~(D409V/D409V)) exhibits characteristics of synucleinopathies, including progressive accumulation of proteinase K-resistant α-synuclein/ubiquitin aggregates in hippocampal neurons and a coincident memory deficit. Analysis of homozygous (Gba1~(D409V/D409V)) and heterozygous (Gba1~(D409V/+) and Gba1~(+/-)) Gaucher mice indicated that these pathologies are a result of the combination of a loss of glucocerebrosidase activity and a toxic gain-of-function resulting from expression of the mutant enzyme. Importantly, adeno-associated virus-mediated expression of exogenous glucocerebrosidase injected into the hippocampus of Gba1~(D409V/D409V) mice ameliorated both the histopathological and memory aberrations. The data support the contention that mutations in GBA1 can cause Parkinson disease-like α-synuclein pathology, and that rescuing brain glucocerebrosidase activity might represent a therapeutic strategy for GBA1-associated synucleinopathies.
机译:新兴的遗传学和临床证据表明,高雪氏病与帕金森病和路易小体痴呆之间存在联系。在这里,我们提供的证据表明,高雪氏病(Gba1〜(D409V / D409V))小鼠模型表现出突触核病的特征,包括蛋白酶抵抗K的α-突触核蛋白/泛素聚集在海马神经元中的累积积累和同时的记忆缺陷。对纯合子(Gba1〜(D409V / D409V))和杂合子(Gba1〜(D409V / +)和Gba1〜(+/-))Gaucher小鼠的分析表明,这些病理是葡萄糖脑苷脂酶活性和突变酶表达导致的有毒功能获得。重要的是,腺相关病毒介导的Gba1〜(D409V / D409V)小鼠海马中外源性葡萄糖脑苷脂酶的表达改善了组织病理学和记忆异常。数据支持以下论点:GBA1中的突变可引起帕金森病样的α-突触核蛋白病理,并且抢救大脑葡萄糖脑苷脂酶活性可能代表了与GBA1相关的突触核病的治疗策略。

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