Cellular processing of α-synuclein fibrils results in distinct physiological C-terminal truncations with a major cleavage site at residue Glu 114.
Cellular processing of α-synuclein fibrils results in distinct physiological C-terminal truncations with a major cleavage site at residue Glu 114.
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DOI：
10.1016/j.jbc.2023.104912
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发表时间：
2023-07
影响因子：
4.8
通讯作者：
Giasson, Benoit I.
中科院分区：
文献类型：
--
作者：
Quintin, Stephan;Lloyd, Grace M.;Paterno, Giavanna;Xia, Yuxing;Sorrentino, Zachary;Bell, Brach M.;Gorion, Kimberly-Marie;Lee, Edward B.;Prokop, Stefan;Giasson, Benoit I.
α-突触核蛋白（αS）是一种丰富的神经元蛋白，在包括路易体病（LBD）和多系统萎缩（MSA）在内的一系列神经退行性疾病中组装成纤维状病理内含物。病理包涵体的细胞和区域分布在不同的突触核蛋白病之间差异很大，这有助于临床表现的谱。αS羧基(C)端区域的广泛切割与包涵体的形成有关，尽管导致这些修饰的事件及其对病理生物学的影响仍在研究中。αS预形成原纤维在体外和动物疾病模型中均可诱导αS病变的朊病毒样扩散。使用C截断特异性抗体，我们在这里证明了朊病毒样细胞摄取和加工αS预形成的原纤维导致残基103和114的两个主要切割。第三个裂解产物（122 αS）在溶酶体蛋白酶抑制剂的应用中积累。在体外，1-103和1-114 αS在分离和全长αS存在下均能快速而广泛地聚合。1-103 αS在培养细胞中表达时也表现出更广泛的聚集。此外，我们使用在Glu114残基处切割αS的新型抗体，评估LBD和MSA患者死后脑组织x-114 αS的病理变化，以及三种不同的朊病毒样诱导转基因αS小鼠模型。x-114 αS病理分布不同于整体αS病理分布。这些研究揭示了残基114和103截断的αS c的细胞形成和行为，以及x-114 αS病理的疾病依赖分布。
α-synuclein (αS) is an abundant, neuronal protein that assembles into fibrillar pathological inclusions in a spectrum of neurodegenerative diseases that include Lewy body diseases (LBD) and Multiple System Atrophy (MSA). The cellular and regional distributions of pathological inclusions vary widely between different synucleinopathies contributing to the spectrum of clinical presentations. Extensive cleavage within the carboxy (C)-terminal region of αS is associated with inclusion formation, although the events leading to these modifications and the implications for pathobiology are of ongoing study. αS preformed fibrils can induce prion-like spread of αS pathology in both in vitro and animal models of disease. Using C truncation-specific antibodies, we demonstrated here that prion-like cellular uptake and processing of αS preformed fibrils resulted in two major cleavages at residues 103 and 114. A third cleavage product (122 αS) accumulated upon application of lysosomal protease inhibitors. In vitro, both 1-103 and 1-114 αS polymerized rapidly and extensively in isolation and in the presence of full-length αS. 1-103 αS also demonstrated more extensive aggregation when expressed in cultured cells. Furthermore, we used novel antibodies to αS cleaved at residue Glu114, to assess x-114 αS pathology in postmortem brain tissue from patients with LBD and MSA, as well as three different transgenic αS mouse models of prion-like induction. The distribution of x-114 αS pathology was distinct from that of overall αS pathology. These studies reveal the cellular formation and behavior of αS C-truncated at residues 114 and 103 as well as the disease dependent distribution of x-114 αS pathology.
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影响因子：
4.7
作者：
Campbell, BCV;McLean, CA;Li, QX
通讯作者：
Li, QX
影响因子：
12.7
作者：
通讯作者：
--
影响因子：
4.8
作者：
Liu, CW;Giasson, BI;Thomas, PJ
通讯作者：
Thomas, PJ
影响因子：
7.1
作者：
Hass EW;Sorrentino ZA;Xia Y;Lloyd GM;Trojanowski JQ;Prokop S;Giasson BI
通讯作者：
Giasson BI
影响因子：
15.1
作者：
Lloyd GM;Dhillon JS;Gorion KM;Riffe C;Fromholt SE;Xia Y;Giasson BI;Borchelt DR
通讯作者：
Borchelt DR