结节性硬化综合征1患者来源的神经祖细胞的Translatomy分析显示雷帕霉素依赖性和独立性改变。

IF 6.3 1区 医学 Q1 GENETICS & HEREDITY Molecular Autism Pub Date : 2023-10-25 DOI:10.1186/s13229-023-00572-3
Inci S Aksoylu, Pauline Martin, Francis Robert, Krzysztof J Szkop, Nicholas E Redmond, Srirupa Bhattacharyya, Jennifer Wang, Shan Chen, Roberta L Beauchamp, Irene Nobeli, Jerry Pelletier, Ola Larsson, Vijaya Ramesh
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引用次数: 0

摘要

背景:结节性硬化综合征(TSC)是一种由TSC1或TSC2基因突变引起的遗传性神经皮肤疾病,患者经常表现出神经发育(ND)表现,称为TSC相关神经精神障碍(TAND),包括自闭症谱系障碍(ASD)和智力残疾。Hamartin(TSC1)和tuberin(TSC2)蛋白形成雷帕霉素复合物1(mTORC1)信号传导的复合物抑制机制靶标。TSC1或TSC2的缺失激活mTORC1,在几个靶标中,mTORC1通过抑制翻译阻遏物eIF4E结合蛋白来控制蛋白质合成。使用TSC1患者来源的神经祖细胞(NPC),我们最近报道了早期ND表型变化,包括TSC1缺失的NPC中细胞增殖增加和轴突生长改变,这些细胞不受mTORC1抑制剂雷帕霉素的影响。方法:在这里,我们使用多组分析,在转录组水平上量化mRNA丰度和翻译效率的变化,来比较CRISPR编辑的TSC1-null和由一个TSC供体(一个克隆/基因型)产生的CRISPR校正的TSC1-WT NPC。为了评估已确定的基因表达改变的相关性,我们对ASD供体和年龄匹配的对照组的死后大脑进行了多聚体分析。我们进一步比较了在使用变构抑制剂雷帕霉素抑制mTORC1后对NPCs中转录物子集的翻译和早期ND表型的拯救的影响与第三代双空间,mTORC1选择性抑制剂RMC-6272结果:NPC的多聚体图谱显示了许多与TSC1相关的mRNA翻译变化,这些变化在人类ASD大脑中大量重现。此外,尽管雷帕霉素治疗部分逆转了TSC1相关的mRNA翻译改变,但大多数与神经活动/突触调节或ASD相关的基因对雷帕霉素不敏感。相反,RMC-6272治疗抑制了雷帕霉素不敏感的翻译,并逆转了TSC1相关的早期ND表型,包括不受雷帕霉素影响的增殖和轴突生长。结论:我们的工作揭示了TSC1患者来源的NPC中大量的mRNA翻译改变,这些改变概括了ASD脑样本中的mRNA翻译。此外,RMC-6272对TSC1相关但雷帕霉素不敏感的翻译和ND表型的抑制揭示了更有效地靶向mTORC1作为TAND的优越治疗策略的潜在意义。
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Translatome analysis of tuberous sclerosis complex 1 patient-derived neural progenitor cells reveals rapamycin-dependent and independent alterations.

Background: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder caused by mutations in the TSC1 or TSC2 genes, with patients often exhibiting neurodevelopmental (ND) manifestations termed TSC-associated neuropsychiatric disorders (TAND) including autism spectrum disorder (ASD) and intellectual disability. Hamartin (TSC1) and tuberin (TSC2) proteins form a complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. Loss of TSC1 or TSC2 activates mTORC1 that, among several targets, controls protein synthesis by inhibiting translational repressor eIF4E-binding proteins. Using TSC1 patient-derived neural progenitor cells (NPCs), we recently reported early ND phenotypic changes, including increased cell proliferation and altered neurite outgrowth in TSC1-null NPCs, which were unaffected by the mTORC1 inhibitor rapamycin.

Methods: Here, we used polysome profiling, which quantifies changes in mRNA abundance and translational efficiencies at a transcriptome-wide level, to compare CRISPR-edited TSC1-null with CRISPR-corrected TSC1-WT NPCs generated from one TSC donor (one clone/genotype). To assess the relevance of identified gene expression alterations, we performed polysome profiling in postmortem brains from ASD donors and age-matched controls. We further compared effects on translation of a subset of transcripts and rescue of early ND phenotypes in NPCs following inhibition of mTORC1 using the allosteric inhibitor rapamycin versus a third-generation bi-steric, mTORC1-selective inhibitor RMC-6272.

Results: Polysome profiling of NPCs revealed numerous TSC1-associated alterations in mRNA translation that were largely recapitulated in human ASD brains. Moreover, although rapamycin treatment partially reversed the TSC1-associated alterations in mRNA translation, most genes related to neural activity/synaptic regulation or ASD were rapamycin-insensitive. In contrast, treatment with RMC-6272 inhibited rapamycin-insensitive translation and reversed TSC1-associated early ND phenotypes including proliferation and neurite outgrowth that were unaffected by rapamycin.

Conclusions: Our work reveals ample mRNA translation alterations in TSC1 patient-derived NPCs that recapitulate mRNA translation in ASD brain samples. Further, suppression of TSC1-associated but rapamycin-insensitive translation and ND phenotypes by RMC-6272 unveils potential implications for more efficient targeting of mTORC1 as a superior treatment strategy for TAND.

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来源期刊
Molecular Autism
Molecular Autism GENETICS & HEREDITY-NEUROSCIENCES
CiteScore
12.10
自引率
1.60%
发文量
44
审稿时长
17 weeks
期刊介绍: Molecular Autism is a peer-reviewed, open access journal that publishes high-quality basic, translational and clinical research that has relevance to the etiology, pathobiology, or treatment of autism and related neurodevelopmental conditions. Research that includes integration across levels is encouraged. Molecular Autism publishes empirical studies, reviews, and brief communications.
期刊最新文献
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