SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis.
SRSF1-dependent inhibition of C9ORF72-repeat RNA nuclear export: genome-wide mechanisms for neuroprotection in amyotrophic lateral sclerosis.
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SRSF1依赖性抑制C9ORF72重复RNA核输出：肌萎缩侧索硬化症神经保护的全基因组机制
DOI：
10.1186/s13024-021-00475-y
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发表时间：
2021-08-10
影响因子：
15.1
通讯作者：
Hautbergue GM
中科院分区：
文献类型：
--
作者：
Castelli LM;Cutillo L;Souza CDS;Sanchez-Martinez A;Granata I;Lin YH;Myszczynska MA;Heath PR;Livesey MR;Ning K;Azzouz M;Shaw PJ;Guarracino MR;Whitworth AJ;Ferraiuolo L;Milo M;Hautbergue GM
肌萎缩侧索硬化症 (ALS) 中运动神经元的丧失会导致进行性瘫痪和死亡。在多种细胞通路中发挥作用的数千个 RNA 分子的失调阻碍了神经退行性过程继发下游变化的 ALS 引起改变的识别。这些病理性基因表达变化中有多少以及哪些需要治疗正常化仍然是一个基本问题。在这里，我们研究了 C9ORF72-ALS 患者来源的神经元和果蝇中的全基因组 RNA 变化，以及利用我们的基因治疗方法进行神经保护，该方法特异性抑制病理性 C9ORF72 重复转录本的 SRSF1 依赖性核输出。这是一项关键研究，旨在评估 (i) SRSF1 部分缺失的整体安全性和有效性，SRSF1 是参与基因表达的蛋白质家族的成员，以及 (ii) 识别神经保护性 RNA 变化的独特机会。我们的研究表明，对 2257 个病理变化中的 362 个转录本进行操作，除了抑制重复转录本的核输出外，还足以赋予 C9ORF72-ALS 患者来源的神经元神经保护作用。特别是，90 个疾病改变转录物的表达在神经保护后完全恢复，从而导致人类 C9ORF72-ALS 疾病修饰基因表达特征的表征。这些发现在患病和神经保护的果蝇转录组中进行了体内进一步研究，突出显示了患者源性神经元中 16 个人类直系同源物保守的 21 个神经保护变化。我们还从功能上验证了这些疾病修饰转录物之一的高神经保护潜力，证明抑制 ALS 上调的人类 KCNN1-3（果蝇 SK）电压门控钾通道直系同源物可减轻人类运动神经元的退化和果蝇运动缺陷。引人注目的是，SRSF1 的部分缺失仅导致一小部分疾病改变的转录本发生表达变化，这表明并非所有 RNA 改变都需要标准化，并且基因治疗方法在上述临床前模型中是安全的，因为它不会破坏全局基因表达。这种干预的功效也在全基因组水平上得到了验证，C9ORF72-ALS 中受影响的绝大多数生物过程中的转录本都受到调节。最后，鉴定在疾病状态和神经保护作用下修改的关键RNA变化的特征签名也提供了潜在的新治疗靶点和生物标志物。在线版本包含可在 10.1186/s13024-021-00475-y 获取的补充材料。
Loss of motor neurons in amyotrophic lateral sclerosis (ALS) leads to progressive paralysis and death. Dysregulation of thousands of RNA molecules with roles in multiple cellular pathways hinders the identification of ALS-causing alterations over downstream changes secondary to the neurodegenerative process. How many and which of these pathological gene expression changes require therapeutic normalisation remains a fundamental question. Here, we investigated genome-wide RNA changes in C9ORF72-ALS patient-derived neurons and Drosophila, as well as upon neuroprotection taking advantage of our gene therapy approach which specifically inhibits the SRSF1-dependent nuclear export of pathological C9ORF72-repeat transcripts. This is a critical study to evaluate (i) the overall safety and efficacy of the partial depletion of SRSF1, a member of a protein family involved itself in gene expression, and (ii) a unique opportunity to identify neuroprotective RNA changes. Our study shows that manipulation of 362 transcripts out of 2257 pathological changes, in addition to inhibiting the nuclear export of repeat transcripts, is sufficient to confer neuroprotection in C9ORF72-ALS patient-derived neurons. In particular, expression of 90 disease-altered transcripts is fully reverted upon neuroprotection leading to the characterisation of a human C9ORF72-ALS disease-modifying gene expression signature. These findings were further investigated in vivo in diseased and neuroprotected Drosophila transcriptomes, highlighting a list of 21 neuroprotective changes conserved with 16 human orthologues in patient-derived neurons. We also functionally validated the high neuroprotective potential of one of these disease-modifying transcripts, demonstrating that inhibition of ALS-upregulated human KCNN1–3 (Drosophila SK) voltage-gated potassium channel orthologs mitigates degeneration of human motor neurons and Drosophila motor deficits. Strikingly, the partial depletion of SRSF1 leads to expression changes in only a small proportion of disease-altered transcripts, indicating that not all RNA alterations need normalization and that the gene therapeutic approach is safe in the above preclinical models as it does not disrupt globally gene expression. The efficacy of this intervention is also validated at genome-wide level with transcripts modulated in the vast majority of biological processes affected in C9ORF72-ALS. Finally, the identification of a characteristic signature with key RNA changes modified in both the disease state and upon neuroprotection also provides potential new therapeutic targets and biomarkers. The online version contains supplementary material available at 10.1186/s13024-021-00475-y.
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影响因子：
56.9
作者：
Cheng, J;Kapranov, P;Gingeras, TR
通讯作者：
Gingeras, TR
影响因子：
16.6
作者：
Du, Zhong-Wei;Chen, Hong;Liu, Huisheng;Lu, Jianfeng;Qian, Kun;Huang, CindyTzu-Ling;Zhong, Xiaofen;Fan, Frank;Zhang, Su-Chun
通讯作者：
Zhang, Su-Chun
影响因子：
16
作者：
Anczuków O;Akerman M;Cléry A;Wu J;Shen C;Shirole NH;Raimer A;Sun S;Jensen MA;Hua Y;Allain FH;Krainer AR
通讯作者：
Krainer AR
DOI：
10.1093/brain/awu120
发表时间：
2014-07
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Cooper-Knock J;Walsh MJ;Higginbottom A;Robin Highley J;Dickman MJ;Edbauer D;Ince PG;Wharton SB;Wilson SA;Kirby J;Hautbergue GM;Shaw PJ
通讯作者：
Shaw PJ
DOI：
10.1007/978-3-319-60733-7_6
发表时间：
2017-01-01
期刊：
PERSONALISED MEDICINE: LESSONS FROM NEURODEGENERATION TO CANCER
影响因子：
--
作者：
Hautbergue, Guillaume M.
通讯作者：
Hautbergue, Guillaume M.