Ischiropoulos Harry
Stokes Research Institute, Department of Biochemistry and Biophysics, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Ann N Y Acad Sci. 2003 Jun;991:93-100. doi: 10.1111/j.1749-6632.2003.tb07466.x.
Hallmark lesions of neurodegenerative synucleinopathies contain alpha-synuclein (alpha-syn) that is modified by nitration of tyrosine residues and possibly by dityrosine cross-linking to generated stable oligomers. Data gathered from in vitro experiments and from model systems of cells transfected with wild-type and mutant alpha-syn revealed that conditions resulting in alpha-syn nitration also induce formation of alpha-syn inclusions with similar biochemical characteristics to protein extracted from human lesions. The detection of tyrosine-nitrated alpha-syn signifies the formation of reactive nitrogen species capable of both radical and electrophilic attack on aromatic residues as well as nucleophilic additions and oxidations. The cellular sources and biochemical reactivity of reactive nitrogen species in the central nervous system remain largely unknown, but kinetically fast reactions of nitric oxide with superoxide to form peroxynitrite as well as enzymatic one-electron oxidation of nitrite are two important sources of reactive nitrogen species. Based on these findings a model is proposed where the process of fibrilization can be differentially affected by oxidants and nitrating species. Posttranslational modifications of alpha-syn by reactive nitrogen species inhibits fibril formation and results in urea- and SDS- insoluble, protease-resistant alpha-syn aggregates that maybe responsible for cellular toxicity.
神经退行性突触核蛋白病的标志性病变包含经酪氨酸残基硝化修饰、可能还经二酪氨酸交联形成稳定寡聚体的α-突触核蛋白（α-syn）。从体外实验以及用野生型和突变型α-syn转染的细胞模型系统收集的数据表明，导致α-syn硝化的条件也会诱导形成与从人类病变中提取的蛋白质具有相似生化特性的α-syn包涵体。酪氨酸硝化的α-syn的检测表明能够对芳香族残基进行自由基和亲电攻击以及亲核加成和氧化的活性氮物种的形成。中枢神经系统中活性氮物种的细胞来源和生化反应性在很大程度上仍不清楚，但一氧化氮与超氧化物快速反应形成过氧亚硝酸盐以及亚硝酸盐的酶促单电子氧化是活性氮物种的两个重要来源。基于这些发现，提出了一个模型，其中纤维化过程可能受到氧化剂和硝化物种的不同影响。活性氮物种对α-syn的翻译后修饰会抑制纤维形成，并导致尿素和十二烷基硫酸钠不溶性、蛋白酶抗性的α-syn聚集体，这些聚集体可能是细胞毒性的原因。
