SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington's disease phenotypes
SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington's disease phenotypes
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DOI：
10.1093/brain/awab186
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发表时间：
2021-05-11
期刊：
影响因子：
14.5
通讯作者：
Valenza, Marta
中科院分区：
文献类型：
--
作者：
Birolini, Giulia;Verlengia, Gianluca;Valenza, Marta
大脑胆固醇主要由星形胶质细胞产生，对神经元功能非常重要。在亨廷顿病小鼠模型中，它的生物合成严重减少。一种可能的机制是转录因子类固醇调节元件结合蛋白2(SREBP2)的核转位减少，从而减少了SREBP2控制的基因在胆固醇生物合成途径中的激活。在这里，我们评估了一种基于单侧纹状体内注射重组腺相关病毒2/5(AAV2/5)并特异性针对星形胶质细胞并携带转录活性的人SREBP2 N端片段(HSREBP2)的基因治疗的有效性。在R6/2亨廷顿病小鼠纹状体胶质细胞中hSREBP2的表达激活了胆固醇生物合成途径基因的转录，恢复了突触传递，逆转了多巴胺受体D2(Drd2)转录水平的下降，清除突变的猎杀蛋白聚集体并减轻行为缺陷。我们的结论是，胶质细胞的SREBP2参与了亨廷顿病的脑发病机制，基于AAV的SREBP2向星形胶质细胞的传递抵消了该疾病的关键特征。
Brain cholesterol is produced mainly by astrocytes and is important for neuronal function. Its biosynthesis is severely reduced in mouse models of Huntington's disease. One possible mechanism is a diminished nuclear translocation of the transcription factor sterol regulatory element-binding protein 2 (SREBP2) and, consequently, reduced activation of SREBP2-controlled genes in the cholesterol biosynthesis pathway.Here we evaluated the efficacy of a gene therapy based on the unilateral intra-striatal injection of a recombinant adeno-associated virus 2/5 (AAV2/5) targeting astrocytes specifically and carrying the transcriptionally active Nterminal fragment of human SREBP2 (hSREBP2).Robust hSREBP2 expression in striatal glial cells in R6/2 Huntington's disease mice activated the transcription of cholesterol biosynthesis pathway genes, restored synaptic transmission, reversed dopamine receptor D2 (Drd2) transcript levels decline, cleared mutant huntingtin aggregates and attenuated behavioural deficits. We conclude that glial SREBP2 participates in Huntington's disease brain pathogenesis in uiuo and that AAV-based delivery of SREBP2 to astrocytes counteracts key features of the disease.