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A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies
Acta Neuropathologica ( IF 9.3 ) Pub Date : 2021-07-26 , DOI: 10.1007/s00401-021-02349-5
Maike Hartlage-Rübsamen 1 , Alexandra Bluhm 1 , Sandra Moceri 2 , Lisa Machner 3 , Janett Köppen 3 , Mathias Schenk 3 , Isabel Hilbrich 1 , Max Holzer 1 , Martin Weidenfeller 4 , Franziska Richter 5 , Roland Coras 6 , Geidy E Serrano 7 , Thomas G Beach 7 , Stephan Schilling 3 , Stephan von Hörsten 2 , Wei Xiang 4 , Anja Schulze 3 , Steffen Roßner 1
Affiliation  

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may—in analogy to pGlu-Aβ peptides in Alzheimer’s disease—act as a seed for pathogenic protein aggregation.



中文翻译:

在人类突触核蛋白病中鉴定的谷氨酰胺环化酶催化的 α-突触核蛋白修饰

帕金森病 (PD) 是一种进行性神经退行性疾病,其神经病理学特征是黑质 (SN) 的多巴胺能神经元变性和形成由聚集的 α-突触核蛋白组成的路易体和路易神经突。显示基质金属蛋白酶对 α-突触核蛋白的蛋白水解可促进其聚集并影响细胞活力。其中一个蛋白水解片段 Gln79-α-突触核蛋白在其 N 端具有谷氨酰胺残基。我们认为谷氨酰胺环化酶 (QC) 可以催化焦谷氨酸 (pGlu)79-α-突触核蛋白的形成,从而促进人类突触核蛋白病中 α-突触核蛋白的聚集和降解。在这里,使用酶测定法和质谱法显示了通过 QC 将 Gln79-α-突触核蛋白转化为 pGlu 形式的动力学特征。硫黄素 T 测定和电子显微镜显示 pGlu79-α-突触核蛋白形成原纤维的潜力降低。然而,尺寸排阻色谱和细胞活力测定显示 pGlu79-α-突触核蛋白形成具有高神经毒性的寡聚体的倾向增加。在野生型小鼠的大脑中,多巴胺能 SN 神经元共表达 QC 和 α-突触核蛋白。使用针对 pGlu 修饰的 α-突触核蛋白新表位的特异性抗体,在两个具有人类 α-突触核蛋白过表达的转基因小鼠系的大脑中检测到 pGlu79-α-突触核蛋白聚集体与 QC 相关。在路易体受试者的 PD 和痴呆的人脑样本中,pGlu79-α-突触核蛋白被证明存在于 SN 神经元、许多路易体和营养不良的神经突中。重要的,pGlu79-α-突触核蛋白与人类 SN 复合物中的酶 QC 存在空间共现,并且 QC 与神经病理学结构有明确的关联。我们得出结论,QC 催化人类突触核蛋白病中易发生寡聚体的 pGlu79-α-突触核蛋白的形成,类似于阿尔茨海默病中的 pGlu-Aβ 肽,这可能充当致病蛋白聚集的种子。

更新日期:2021-07-26
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