Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN.
Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN.
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DOI：
10.1083/jcb.202106080
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发表时间：
2022-02-07
期刊：
影响因子：
--
通讯作者：
Segal RA
中科院分区：
文献类型：
--
作者：
Li Y;Pazyra-Murphy MF;Avizonis D;de Sá Tavares Russo M;Tang S;Chen CY;Hsueh YP;Bergholz JS;Jiang T;Zhao JJ;Zhu J;Ko KW;Milbrandt J;DiAntonio A;Segal RA
Li等人将cADPR确定为预防紫杉醇诱导的周围神经病变（PIPN）的治疗靶点。作者表明，紫杉醇触发Sarm1依赖性cADPR的产生，导致轴突钙增加和变性。cADPR拮抗剂在体外和体内防止PIPN，而不降低紫杉醇的抗肿瘤功效。癌症患者经常发生化疗诱导的周围神经病变（CIPN），这是一种疼痛和持久的疾病，伴有严重的躯体感觉缺陷。没有有效的治疗方法来预防或治疗这种疾病。病理学上，CIPN的特征在于从感觉神经元的表皮内神经末梢开始并以逆行方式进展的“回死”轴突病。钙调节异常构成CIPN中的关键事件，但尚不清楚诸如紫杉醇的化疗如何改变轴突内钙并引起变性。在这里，我们证明，紫杉醇触发Sarm1依赖的cADPR生产在远端轴突，促进轴突内钙流从细胞内和细胞外钙库。cADPR信号传导的遗传或药理学拮抗剂可预防紫杉醇诱导的轴突变性和异常性疼痛症状，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变性，并表明靶向cADPR信号转导为治疗紫杉醇诱导的周围神经病变（PIPN）提供了一种潜在的治疗方法。
Li et al. identify cADPR as a therapeutic target for preventing paclitaxel-induced peripheral neuropathy (PIPN). The authors show that paclitaxel triggers Sarm1-dependent cADPR production, causing increased axonal calcium and degeneration. cADPR antagonists protect against PIPN in vitro and in vivo, without mitigating paclitaxel’s anti-neoplastic efficacy. 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).
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影响因子：
15.3
作者：
Geisler, Stefanie;Huang, Shay X.;Milbrandt, Jeffrey
通讯作者：
Milbrandt, Jeffrey
影响因子：
16.2
作者：
Essuman K;Summers DW;Sasaki Y;Mao X;DiAntonio A;Milbrandt J
通讯作者：
Milbrandt J
DOI：
10.1083/jcb.201008050
发表时间：
2011-05-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen CY;Lin CW;Chang CY;Jiang ST;Hsueh YP
通讯作者：
Hsueh YP
DOI：
10.1016/j.bbrc.2006.05.042
发表时间：
2006-07-14
影响因子：
3.1
作者：
Aksoy, Pinar;White, Thomas A.;Chini, Eduardo N.
通讯作者：
Chini, Eduardo N.
影响因子：
4.8
作者：
Benbow, Jennifer H.;Mann, Taylor;Ehrlich, Barbara E.
通讯作者：
Ehrlich, Barbara E.