Nitric oxide signaling is disrupted in the yeast model for Batten disease.
Nitric oxide signaling is disrupted in the yeast model for Batten disease.
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DOI：
10.1091/mbc.e06-11-1053
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发表时间：
2007-07
影响因子：
3.3
通讯作者：
Nuno S. Osório;A. Carvalho;A. Almeida;S. Padilla-Lopez;C. Leão;J. Laranjinha;P. Ludovico;D. Pearce;F. Rodrigues
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文献类型：
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作者：
Nuno S. Osório;A. Carvalho;A. Almeida;S. Padilla-Lopez;C. Leão;J. Laranjinha;P. Ludovico;D. Pearce;F. Rodrigues
幼年型神经元蜡样脂褐素沉积症 (JNCL) 或巴顿病是由 CLN3 基因突变引起的，其特征是脂色素在多种细胞类型的溶酶体中积聚以及广泛的神经元死亡。我们报告说，缺乏人类 CLN3 同源物 BTN1 的 JNCL (btn1-Delta) 酵母模型增强了对甲萘醌产生的氧化应激的抵抗力。人类 CLN3 的表达补充了 btn1-Delta 表型，并且等效的 Btn1p/Cln3 突变与 JNCL 严重程度相关。我们表明，先前报道的 btn1-Delta 中 L-精氨酸水平降低限制了生理和氧化应激条件下一氧化氮 (.NO) 的合成。 .NO 合成中的这种缺陷似乎抑制了酵母甲萘醌诱导的细胞凋亡所需的信号传导，从而解释了 btn1-Delta 抗性增加的表型。我们认为，在 JNCL 中，由于 Cln3 功能缺失直接导致合成 .NO 的能力有限可能会导致该疾病的病理学。
The juvenile form of neuronal ceroid lipofuscinoses (JNCLs), or Batten disease, results from mutations in the CLN3 gene, and it is characterized by the accumulation of lipopigments in the lysosomes of several cell types and by extensive neuronal death. We report that the yeast model for JNCL (btn1-Delta) that lacks BTN1, the homologue to human CLN3, has increased resistance to menadione-generated oxidative stress. Expression of human CLN3 complemented the btn1-Delta phenotype, and equivalent Btn1p/Cln3 mutations correlated with JNCL severity. We show that the previously reported decreased levels of L-arginine in btn1-Delta limit the synthesis of nitric oxide (.NO) in both physiological and oxidative stress conditions. This defect in .NO synthesis seems to suppress the signaling required for yeast menadione-induced apoptosis, thus explaining btn1-Delta phenotype of increased resistance. We propose that in JNCL, a limited capacity to synthesize .NO directly caused by the absence of Cln3 function may contribute to the pathology of the disease.