Extensive Anti-CoA Immunostaining in Alzheimer's Disease and Covalent Modification of Tau by a Key Cellular Metabolite Coenzyme A.
Extensive Anti-CoA Immunostaining in Alzheimer's Disease and Covalent Modification of Tau by a Key Cellular Metabolite Coenzyme A.
复制标题
DOI：
10.3389/fncel.2021.739425
复制
发表时间：
2021
影响因子：
5.3
通讯作者：
Gout I
中科院分区：
文献类型：
--
作者：
Lashley T;Tossounian MA;Costello Heaven N;Wallworth S;Peak-Chew S;Bradshaw A;Cooper JM;de Silva R;Srai SK;Malanchuk O;Filonenko V;Koopman MB;Rüdiger SGD;Skehel M;Gout I
阿尔茨海默病（AD）是一种神经退行性疾病，占痴呆病例的至少三分之二。遗传、表观遗传和环境触发因素的组合被广泛认为是AD发病和发展的原因。越来越多的证据表明，氧化应激和能量代谢失调在AD发病机制中起重要作用，导致神经元功能障碍和死亡。氧化还原诱导的蛋白质修饰已在AD患者的脑中报道，表明过度的氧化损伤。辅酶A（CoA）是多种代谢途径、基因表达调节和神经递质生物合成所必需的。动物模型中CoA生物合成的失调和参与CoA生物合成途径的人类基因的先天性突变与神经变性有关。最近的研究已经揭示了CoA的抗氧化功能，涉及在细胞对氧化或代谢应激的反应中通过该辅因子（CoAlation）的共价蛋白修饰。已显示蛋白质结合既调节修饰蛋白质的活性又保护半胱氨酸残基免于不可逆的过氧化。在这项研究中，使用高度特异性抗CoA单克隆抗体的免疫组织化学分析来揭示许多神经退行性疾病中的蛋白质CoAlation，这在AD中尤其常见。此外，蛋白质CoAlation始终与tau阳性神经元缠结共定位，支持AD的关键病理学标志之一。AD脑组织中tau和CoA抗体的双重免疫组织化学染色显示两种免疫反应信号的共定位。此外，发现重组2N 3R和2N 4 R tau同种型在体外被CoAlated，并且通过质谱将CoAlation位点定位到位于微管结合区的保守半胱氨酸322。我们还报道了可逆的H_2O_2诱导的重组2N_3R的二聚化，这是由CoAlation抑制。此外，在二酰胺处理的HEK 293/Pank 1 β细胞中观察到瞬时表达的2N 4 R tau的聚集。总之，这项研究首次证明了AD脑样本中广泛的抗CoA免疫反应性，其发生在类似神经纤维缠结和神经纤维丝的结构中。半胱氨酸322处重组tau的共价修饰表明，CoAlation可能在保护氧化还原敏感性tau半胱氨酸免受不可逆过度氧化方面发挥重要作用，并可能调节其乙酰转移酶活性和功能相互作用。
Alzheimer’s disease (AD) is a neurodegenerative disorder, accounting for at least two-thirds of dementia cases. A combination of genetic, epigenetic and environmental triggers is widely accepted to be responsible for the onset and development of AD. Accumulating evidence shows that oxidative stress and dysregulation of energy metabolism play an important role in AD pathogenesis, leading to neuronal dysfunction and death. Redox-induced protein modifications have been reported in the brain of AD patients, indicating excessive oxidative damage. Coenzyme A (CoA) is essential for diverse metabolic pathways, regulation of gene expression and biosynthesis of neurotransmitters. Dysregulation of CoA biosynthesis in animal models and inborn mutations in human genes involved in the CoA biosynthetic pathway have been associated with neurodegeneration. Recent studies have uncovered the antioxidant function of CoA, involving covalent protein modification by this cofactor (CoAlation) in cellular response to oxidative or metabolic stress. Protein CoAlation has been shown to both modulate the activity of modified proteins and protect cysteine residues from irreversible overoxidation. In this study, immunohistochemistry analysis with highly specific anti-CoA monoclonal antibody was used to reveal protein CoAlation across numerous neurodegenerative diseases, which appeared particularly frequent in AD. Furthermore, protein CoAlation consistently co-localized with tau-positive neurofibrillary tangles, underpinning one of the key pathological hallmarks of AD. Double immunihistochemical staining with tau and CoA antibodies in AD brain tissue revealed co-localization of the two immunoreactive signals. Further, recombinant 2N3R and 2N4R tau isoforms were found to be CoAlated in vitro and the site of CoAlation mapped by mass spectrometry to conserved cysteine 322, located in the microtubule binding region. We also report the reversible H2O2-induced dimerization of recombinant 2N3R, which is inhibited by CoAlation. Moreover, CoAlation of transiently expressed 2N4R tau was observed in diamide-treated HEK293/Pank1β cells. Taken together, this study demonstrates for the first time extensive anti-CoA immunoreactivity in AD brain samples, which occurs in structures resembling neurofibrillary tangles and neuropil threads. Covalent modification of recombinant tau at cysteine 322 suggests that CoAlation may play an important role in protecting redox-sensitive tau cysteine from irreversible overoxidation and may modulate its acetyltransferase activity and functional interactions.
登录
查看更多内容
DOI：
10.1083/jcb.101.4.1371
发表时间：
1985-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Binder LI;Frankfurter A;Rebhun LI
通讯作者：
Rebhun LI
影响因子：
4.2
作者：
BRASS, EP;TAHILIANI, AG;STABLER, SP
通讯作者：
STABLER, SP
影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA