Are alpha-synuclein fragments novel substrates of glutaminyl cyclase?

谷氨酰环化酶（QC）被证明是阿尔茨海默病患者大脑中产生高神经毒性Abeta肽变体的先决条件。这样的pGlu- Abeta肽具有更强的抗降解性，显示出较高的聚集倾向，并且可以共同聚集未经修饰的Abeta肽。因此，表达QC的神经元被认为代表了脆弱的神经元群体。提出的研究计划是基于我们在男性和小鼠的黑质神经元中发现了显著的QC表达，以及QC形成了pGlu-α-突触核蛋白片段。因此，我们想解决以下问题：(i)帕金森病患者大脑中QC的浓度和/或活性是否增加？（ii）不同α-synuclein片段是否为QC底物？（iii）这些pGlu-α-synuclein肽的聚集特性是什么？（iv）这些pGlu-α-突触核蛋白肽是否存在于帕金森病患者的大脑中？(v)小鼠脑内QC过表达或敲除是否影响pGlu-α-突触核蛋白肽的浓度？回答这些问题将有助于阐明帕金森病的新病理机制，并发现导致多巴胺能神经元变性的未知因素。

The enzyme glutaminyl cyclase (QC) was demonstrated to be a prerequisite for the generation of highly neurotoxic Abeta peptide variants in brains of Alzheimer’s disease patients. Such pGlu- Abeta peptides are more resistant to degradation, display a high tendency to aggregate and can co-aggregate unmodified Abeta peptides. Thus, neurons which express QC are thought to represent vulnerable neuronal populations. The proposed research programme is based on our discovery of significant QC expression by substantia nigra neurons of men and mice and of the formation of a pGlu-α-synuclein fragment by QC. Therefore, we would like to address the following questions: (i) Is the concentration and/or activity of QC increased in brain of Parkinson’s disease patients? (ii) Are different α-synuclein fragments QC substrates? (iii) What are the aggregation characteristics of such pGlu-α-synuclein peptides? (iv) Are these pGlu-α-synuclein peptides present in brains of Parkinson’s disease patients? (v) Are the concentrations of pGlu-α-synuclein peptides affected by QC overexpression or knock-out in mouse brain? Answering these questions will help to elucidate novel pathological mechanisms underlying Parkinson’s disease and to discover yet unknown factors contributing to dopaminergic neuronal degeneration.