<br>PolyGR 和 polyPR 敲入小鼠在 C9orf72 ALS/FTD 神经元中揭示了保守的神经保护性细胞外基质特征,Nature Neuroscience

当前位置： X-MOL 学术 › Nat. Neurosci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

PolyGR 和 polyPR 敲入小鼠在 C9orf72 ALS/FTD 神经元中揭示了保守的神经保护性细胞外基质特征
Nature Neuroscience ( IF 21.2 ) Pub Date : 2024-02-29 , DOI: 10.1038/s41593-024-01589-4
Carmelo Milioto _{1,

2} , Mireia Carcolé _{1,

2} , Ashling Giblin _{1,

2,

3} , Rachel Coneys _{1,

2} , Olivia Attrebi _{1,

2} , Mhoriam Ahmed ₄ , Samuel S Harris ₁ , Byung Il Lee ₁ , Mengke Yang ₁ , Robert A Ellingford ₁ , Raja S Nirujogi _{5,

6} , Daniel Biggs ₇ , Sally Salomonsson _{1,

2} , Matteo Zanovello ₄ , Paula de Oliveira _{1,

2} , Eszter Katona _{1,

2} , Idoia Glaria _{1,

2,

8} , Alla Mikheenko _{1,

2,

4} , Bethany Geary _{5,

6} , Evan Udine ₉ , Deniz Vaizoglu _{1,

2} , Sharifah Anoar ₃ , Khrisha Jotangiya _{1,

2} , Gerard Crowley ₁ , Demelza M Smeeth _{1,

2} , Mirjam L Adams _{1,

2} , Teresa Niccoli ₃ , Rosa Rademakers _{10,

11} , Marka van Blitterswijk ₉ , Anny Devoy ₁₂ , Soyon Hong ₁ , Linda Partridge ₃ , Alyssa N Coyne _{13,

14} , Pietro Fratta _{4,

15} , Dario R Alessi _{5,

6} , Ben Davies _{7,

16} , Marc Aurel Busche ₁ , Linda Greensmith _{4,

15} , Elizabeth M C Fisher _{4,

15} , Adrian M Isaacs _{1,

2,

15}

Affiliation

UK Dementia Research Institute, University College London, London, UK.
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
UCL Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK.
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Research Support Service, Institute of Agrobiotechnology, CSIC-Government of Navarra, Mutilva, Spain.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
UK Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, London, UK.
Francis Crick Institute, London, UK.

二肽重复蛋白是 C9orf72 肌萎缩侧索硬化症（C9ALS）/额颞叶痴呆（FTD）病理学的主要致病特征，但其生理影响尚未完全确定。在这里，我们生成了 C9orf72 二肽重复序列敲入小鼠模型，其特征是表达 400 个密码子优化的 polyGR 或 polyPR 重复序列，以及杂合 C9orf72 还原。（GR）400 和（PR）400 敲入小鼠概括了 C9ALS/FTD 的关键特征，包括皮层神经元过度兴奋、年龄依赖性脊髓运动神经元丧失和进行性运动功能障碍。定量蛋白质组学显示（GR）400 和（PR）400 脊髓细胞外基质（ECM）蛋白增加，其中胶原 COL6A1 蛋白增加最多。TGF-β1 是该 ECM 特征的最预测调节因子之一，人诱导多能干细胞神经元中的 polyGR 表达足以诱导 TGF-β1，其次是 COL6A1。在 polyGR 模型果蝇中敲低 TGF-β1 或 COL6A1 直系同源物加剧了神经退行性变，而 TGF-β1 或 COL6A1 在 C9ALS/FTD 患者诱导的多能干细胞衍生运动神经元中的表达可防止谷氨酸诱导的细胞死亡。总而言之，我们的研究结果揭示了 C9ALS/FTD 中的神经保护和保守的 ECM 特征。

"点击查看英文标题和摘要"

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons

Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.

更新日期：2024-03-03

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南