New links between SOD1 and metabolic dysfunction from a yeast model of amyotrophic lateral sclerosis.
New links between SOD1 and metabolic dysfunction from a yeast model of amyotrophic lateral sclerosis.
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DOI：
10.1242/jcs.190298
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发表时间：
2016-11-01
影响因子：
4
通讯作者：
Gourlay CW
中科院分区：
文献类型：
--
作者：
Bastow EL;Peswani AR;Tarrant DS;Pentland DR;Chen X;Morgan A;Staniforth GL;Tullet JM;Rowe ML;Howard MJ;Tuite MF;Gourlay CW
许多基因与家族形式的致命运动神经元疾病肌萎缩侧索硬化症（ALS）有关。编码超氧化物歧化酶1 （SOD1）的基因中有超过150个突变与ALS有关，但为什么这些突变导致ALS相关的细胞功能障碍尚不清楚。在这项研究中，我们确定了als相关的SOD1突变如何导致酵母酵母细胞健康的变化。我们发现驱动细胞功能障碍的不是聚集体的积累，而是Sod1蛋白稳定性的丧失。Sod1不稳定的毒性作用与线粒体功能丧失或活性氧产生增加无关，而是阻止液泡酸化，扰乱代谢调节并促进衰老。SOD1突变体毒性功能获得的核心是无法调节氨基酸的生物合成。我们还报道了补充亮氨酸可以改善秀丽隐杆线虫ALS模型的运动功能。我们的数据表明，代谢功能障碍在酵母菌和蠕虫ALS模型中sod1介导的毒性中起重要作用。摘要：在一种新的ALS酵母模型中，我们首次发现Sod1突变可导致形成破坏代谢调节的有毒可溶性蛋白。
A number of genes have been linked to familial forms of the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). Over 150 mutations within the gene encoding superoxide dismutase 1 (SOD1) have been implicated in ALS, but why such mutations lead to ALS-associated cellular dysfunction is unclear. In this study, we identify how ALS-linked SOD1 mutations lead to changes in the cellular health of the yeast Saccharomyces cerevisiae. We find that it is not the accumulation of aggregates but the loss of Sod1 protein stability that drives cellular dysfunction. The toxic effect of Sod1 instability does not correlate with a loss of mitochondrial function or increased production of reactive oxygen species, but instead prevents acidification of the vacuole, perturbs metabolic regulation and promotes senescence. Central to the toxic gain-of-function seen with the SOD1 mutants examined was an inability to regulate amino acid biosynthesis. We also report that leucine supplementation results in an improvement in motor function in a Caenorhabditis elegans model of ALS. Our data suggest that metabolic dysfunction plays an important role in Sod1-mediated toxicity in both the yeast and worm models of ALS. Summary: In a new yeast model of ALS we have discovered for the first time that mutations in Sod1 can lead to the formation of toxic, soluble proteins that disrupt metabolic regulation.
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影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
3.5
作者：
Graffmo, Karin S.;Forsberg, Karin;Brannstrom, Thomas
通讯作者：
Brannstrom, Thomas
影响因子：
6.1
作者：
Ghadge, GD;Wang, LJ;Roos, RP
通讯作者：
Roos, RP
影响因子：
1.7
作者：
Canton, T;Pratt, J;Boireau, A
通讯作者：
Boireau, A
影响因子：
3.7
作者：
Kepp KP
通讯作者：
Kepp KP