Minniti Alicia N, Arrazola Macarena S, Bravo-Zehnder Marcela, Ramos Francisca, Inestrosa Nibaldo C, Aldunate Rebeca
1 Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile , Santiago, Chile .
Antioxid Redox Signal. 2015 Jan 1;22(1):48-62. doi: 10.1089/ars.2013.5803.
To examine the role of the enzyme methionine sulfoxide reductase A-1 (MSRA-1) in amyloid-β peptide (Aβ)-peptide aggregation and toxicity in vivo, using a Caenorhabditis elegans model of the human amyloidogenic disease inclusion body myositis.
MSRA-1 specifically reduces oxidized methionines in proteins. Therefore, a deletion of the msra-1 gene was introduced into transgenic C. elegans worms that express the Aβ-peptide in muscle cells to prevent the reduction of oxidized methionines in proteins. In a constitutive transgenic Aβ strain that lacks MSRA-1, the number of amyloid aggregates decreases while the number of oligomeric Aβ species increases. These results correlate with enhanced synaptic dysfunction and mislocalization of the nicotinic acetylcholine receptor ACR-16 at the neuromuscular junction (NMJ).
This approach aims at modulating the oxidation of Aβ in vivo indirectly by dismantling the methionine sulfoxide repair system. The evidence presented here shows that the absence of MSRA-1 influences Aβ aggregation and aggravates locomotor behavior and NMJ dysfunction. The results suggest that therapies which boost the activity of the Msr system could have a beneficial effect in managing amyloidogenic pathologies.
The absence of MSRA-1 modulates Aβ-peptide aggregation and increments its deleterious effects in vivo.
利用人类淀粉样变性疾病包涵体肌炎的秀丽隐杆线虫模型，研究甲硫氨酸亚砜还原酶A-1（MSRA-1）在淀粉样β肽（Aβ）聚集及体内毒性中的作用。
MSRA-1特异性还原蛋白质中的氧化甲硫氨酸。因此，将msra-1基因缺失引入在肌肉细胞中表达Aβ肽的转基因秀丽隐杆线虫，以阻止蛋白质中氧化甲硫氨酸的还原。在缺乏MSRA-1的组成型转基因Aβ菌株中，淀粉样聚集体数量减少，而寡聚Aβ种类数量增加。这些结果与神经肌肉接头（NMJ）处突触功能障碍增强和烟碱型乙酰胆碱受体ACR-16定位错误相关。
该方法旨在通过拆解甲硫氨酸亚砜修复系统间接调节体内Aβ的氧化。此处提供的证据表明，MSRA-1的缺失会影响Aβ聚集，并加重运动行为和NMJ功能障碍。结果表明，增强Msr系统活性的疗法可能对治疗淀粉样变性疾病具有有益效果。
MSRA-1的缺失调节Aβ肽聚集并增加其在体内的有害作用。
