Patient-specific variants of NFU1/NFU-1 disrupt cholinergic signaling in a model of multiple mitochondrial dysfunctions syndrome 1.
Patient-specific variants of NFU1/NFU-1 disrupt cholinergic signaling in a model of multiple mitochondrial dysfunctions syndrome 1.
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NFU1/NFU-1的患者特异性变体在多个线粒体功能障碍综合征1的模型中破坏胆碱能信号传导。
DOI：
10.1242/dmm.049594
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发表时间：
2023-02-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
神经肌肉功能障碍是线粒体疾病的常见特征，并且经常表现为共济失调、痉挛和/或肌张力障碍，所有这些都会严重影响患有线粒体疾病的个体。肌张力障碍是多发性线粒体功能障碍综合征1（MMDS1）最常见的症状之一，MMDS1是一种与致病基因（NFU 1）突变相关的疾病，其损害铁硫簇生物合成。我们已经产生了秀丽隐杆线虫菌株，在C. elegans直系同源物（NFU-1），其导致等位基因特异性功能障碍。这些突变体中的每一个，Gly147Arg和Gly166Cys，都改变了神经肌肉接头处的乙酰胆碱信号，但对活动和运动的影响相反。我们发现Gly147Arg变异体对乙酰胆碱超敏，并且乙酰胆碱释放的敲低挽救了该变异体的几乎所有神经肌肉表型。相比之下，我们发现Gly166Cys变异主要引起突触后乙酰胆碱超敏反应，由于不清楚的机制。这些结果对于了解MMDS1患者的神经肌肉状况和潜在的治疗干预途径非常重要。总结：NFU 1/NFU-1的患者特异性变体影响C. elegans的变异是由于异常的胆碱能信号传导，但变异体对突触前和突触后功能有不同的影响。
Neuromuscular dysfunction is a common feature of mitochondrial diseases and frequently presents as ataxia, spasticity and/or dystonia, all of which can severely impact individuals with mitochondrial diseases. Dystonia is one of the most common symptoms of multiple mitochondrial dysfunctions syndrome 1 (MMDS1), a disease associated with mutations in the causative gene (NFU1) that impair iron–sulfur cluster biogenesis. We have generated Caenorhabditis elegans strains that recreated patient-specific point variants in the C. elegans ortholog (nfu-1) that result in allele-specific dysfunction. Each of these mutants, Gly147Arg and Gly166Cys, have altered acetylcholine signaling at neuromuscular junctions, but opposite effects on activity and motility. We found that the Gly147Arg variant was hypersensitive to acetylcholine and that knockdown of acetylcholine release rescued nearly all neuromuscular phenotypes of this variant. In contrast, we found that the Gly166Cys variant caused predominantly postsynaptic acetylcholine hypersensitivity due to an unclear mechanism. These results are important for understanding the neuromuscular conditions of MMDS1 patients and potential avenues for therapeutic intervention. Summary: Patient-specific variants in NFU1/NFU-1 affect motility and movement in C. elegans due to aberrant cholinergic signaling, but variants have different effects on presynaptic and postsynaptic function.
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影响因子：
5.3
作者：
Campanucci, Veronica A.;Krishnaswamy, Arjun;Cooper, Ellis
通讯作者：
Cooper, Ellis
DOI：
10.1073/pnas.0409009101
发表时间：
2005-03-01
影响因子：
11.1
作者：
Gray, JM;Hill, JJ;Bargmann, CI
通讯作者：
Bargmann, CI
影响因子：
16.2
作者：
Fujiwara, M;Sengupta, P;McIntire, SL
通讯作者：
McIntire, SL
影响因子：
5.3
作者：
Hills, T;Brockie, PJ;Maricq, AV
通讯作者：
Maricq, AV
影响因子：
3.7
作者：
Invernizzi, Federica;Ardissone, Anna;Moroni, Isabella
通讯作者：
Moroni, Isabella