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聚（PR）介导的神经退行性变与核仁应激相关。

poly(PR) mediated neurodegeneration is associated with nucleolar stress.

作者信息

Cicardi M E, Hallgren J H, Mawrie D, Krishnamurthy K, Markandaiah S S, Nelson A T, Kankate V, Anderson E N, Pasinelli P, Pandey U B, Eischen C M, Trotti D

机构信息

Jefferson Weinberg ALS Center.

Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA.

出版信息

bioRxiv. 2023 Feb 16:2023.02.16.528809. doi: 10.1101/2023.02.16.528809.

DOI:10.1101/2023.02.16.528809
PMID:36824930
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9949130/
Abstract

The ALS/FTD-linked intronic hexanucleotide repeat expansion in the gene is translated into dipeptide repeat proteins, among which poly-proline-arginine (PR) displays the most aggressive neurotoxicity and . PR partitions to the nucleus when expressed in neurons and other cell types. Using and primary rat cortical neurons as model systems, we show that by lessening the nuclear accumulation of PR, we can drastically reduce its neurotoxicity. PR accumulates in the nucleolus, a site of ribosome biogenesis that regulates the cell stress response. We examined the effect of nucleolar PR accumulation and its impact on nucleolar function and determined that PR caused nucleolar stress and increased levels of the transcription factor p53. Downregulating p53 levels, either genetically or by increasing its degradation, also prevented PR-mediated neurotoxic phenotypes both in and models. We also investigated whether PR could cause the senescence phenotype in neurons but observed none. Instead, we found induction of apoptosis caspase-3 activation. In summary, we uncovered the central role of nucleolar dysfunction upon PR expression in the context of C9-ALS/FTD.

摘要

与肌萎缩侧索硬化症/额颞叶痴呆（ALS/FTD）相关的该基因内含子六核苷酸重复序列扩增会被翻译为二肽重复蛋白，其中多聚脯氨酸 - 精氨酸（PR）表现出最强的神经毒性。当在神经元和其他细胞类型中表达时，PR会定位于细胞核。利用[具体内容缺失]和原代大鼠皮层神经元作为模型系统，我们发现通过减少PR在细胞核中的积累，可以大幅降低其神经毒性。PR积聚在核仁中，核仁是核糖体生物合成的场所，可调节细胞应激反应。我们研究了核仁中PR积累的影响及其对核仁功能的作用，并确定PR会导致核仁应激并增加转录因子p53的水平。无论是通过基因手段下调p53水平，还是通过增加其降解来下调，都能在[具体内容缺失]和[具体内容缺失]模型中预防PR介导的神经毒性表型。我们还研究了PR是否会导致神经元出现衰老表型，但未观察到。相反，我们发现了凋亡的诱导——半胱天冬酶 - 3激活。总之，我们揭示了在C9 - ALS/FTD背景下，核仁功能障碍在PR表达过程中的核心作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/f127c077fcd6/nihpp-2023.02.16.528809v1-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/f8b0668f8032/nihpp-2023.02.16.528809v1-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/b17f705b9038/nihpp-2023.02.16.528809v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/b35a6d87ffe7/nihpp-2023.02.16.528809v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/406ce3061494/nihpp-2023.02.16.528809v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/9e4b4a08650f/nihpp-2023.02.16.528809v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/93fad42a6acb/nihpp-2023.02.16.528809v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/fe8afd0ab1f7/nihpp-2023.02.16.528809v1-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/dd15ed6323c4/nihpp-2023.02.16.528809v1-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/f127c077fcd6/nihpp-2023.02.16.528809v1-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/f8b0668f8032/nihpp-2023.02.16.528809v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/9fc859d8326c/nihpp-2023.02.16.528809v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/b17f705b9038/nihpp-2023.02.16.528809v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/b35a6d87ffe7/nihpp-2023.02.16.528809v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/406ce3061494/nihpp-2023.02.16.528809v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/9e4b4a08650f/nihpp-2023.02.16.528809v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/93fad42a6acb/nihpp-2023.02.16.528809v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/fe8afd0ab1f7/nihpp-2023.02.16.528809v1-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/dd15ed6323c4/nihpp-2023.02.16.528809v1-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/429d/9949130/f127c077fcd6/nihpp-2023.02.16.528809v1-f0010.jpg

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Loss of lamin-B1 and defective nuclear morphology are hallmarks of astrocyte senescence in vitro and in the aging human hippocampus.核层蛋白 B1 的缺失和核形态缺陷是体外星形胶质细胞衰老和衰老人类海马体的标志。
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