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Sarm1 的激活会产生 cADPR，以增加轴内 Ca++并促进 PIPN 中的轴突退化。

Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN.

机构信息

Department of Neurobiology, Harvard Medical School, Boston, MA.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.

出版信息

J Cell Biol. 2022 Feb 7;221(2). doi: 10.1083/jcb.202106080. Epub 2021 Dec 22.

DOI:10.1083/jcb.202106080
PMID:34935867
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8704956/
Abstract

Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a "dying-back" axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium-modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating paclitaxel-induced peripheral neuropathy (PIPN).

摘要

癌症患者经常会出现化疗引起的周围神经病变（CIPN），这是一种痛苦且持久的疾病，伴有严重的躯体感觉缺陷。目前尚无有效的治疗方法来预防或治疗这种疾病。从病理学上讲，CIPN 的特征是“退行性”轴突病，它始于感觉神经元的表皮内神经末梢，并逆行进展。钙失调是 CIPN 的一个关键事件，但尚不清楚紫杉醇等化疗药物如何改变轴内钙并导致退化。在这里，我们证明紫杉醇在远端轴突中触发 Sarm1 依赖性 cADPR 产生，促进来自细胞内和细胞外钙库的轴内钙流。cADPR 信号的遗传或药理学拮抗剂可预防紫杉醇诱导的轴突退化和痛觉过敏症状，而不会减轻紫杉醇的抗肿瘤疗效。我们的数据表明 cADPR 是一种钙调节因子，可促进紫杉醇诱导的轴突退化，并表明靶向 cADPR 信号可能为治疗紫杉醇引起的周围神经病（PIPN）提供一种潜在的治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/65d3fd2dd784/JCB_202106080_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/559c67832e33/JCB_202106080_GA.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/47c5e35d4fc5/JCB_202106080_FigS3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/1be4d68f637b/JCB_202106080_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/a2a7fcf701eb/JCB_202106080_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/80f6232cba51/JCB_202106080_Fig5.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/fe35d0c2ebfd/JCB_202106080_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/65d3fd2dd784/JCB_202106080_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/559c67832e33/JCB_202106080_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/919af2553c0f/JCB_202106080_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/c30aed6600b2/JCB_202106080_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/4df719ee54bd/JCB_202106080_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/12dab3ba680b/JCB_202106080_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/47c5e35d4fc5/JCB_202106080_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/fe78bc4686b4/JCB_202106080_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/1be4d68f637b/JCB_202106080_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/a2a7fcf701eb/JCB_202106080_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/80f6232cba51/JCB_202106080_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/548e7bf72093/JCB_202106080_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/fe35d0c2ebfd/JCB_202106080_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9c8c/8704956/65d3fd2dd784/JCB_202106080_Fig7.jpg

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3
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