Cycad Genotoxin Methylazoxymethanol Disrupts the Brain Ubiquitin-Proteasome Pathway, Tau and α-Synuclein, as Reported in ALS-PDC.
Cycad Genotoxin Methylazoxymethanol Disrupts the Brain Ubiquitin-Proteasome Pathway, Tau and α-Synuclein, as Reported in ALS-PDC.
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据 ALS-PDC 报道，苏铁基因毒素甲基偶氮甲醇会破坏大脑泛素蛋白酶体通路、Tau 蛋白和 α-突触核蛋白。
DOI：
10.1093/jnen/nlab006
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发表时间：
2021
影响因子：
3.2
通讯作者：
Spencer,PeterS
中科院分区：
文献类型：
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作者：
Kisby,GlenE;Eriksen,JasonL;Chlebowski,AnnaC;Spencer,PeterS
致编辑：在他们最近的JNEN论文（1）和相关文章（2，3）中，Verheijen及其同事证明了在患有肌萎缩性侧索硬化症和帕金森病-痴呆综合征（ALS-PDC）的日本人和关岛人的大脑中存在与神经元缠结（tau蛋白病）相关的泛素-BABR 1（UBBR 1）蛋白。他们指出，UBB β 1是泛素的移码突变体，由分子误读（一种转录突变）产生。UBB β 1是泛素-蛋白酶体系统的剂量依赖性抑制剂，泛素-蛋白酶体系统是细胞内蛋白水解的主要途径。阳性免疫染色也证明了泛素结合蛋白p62，ATG 8和ATG 12，表明自噬途径的异常。基于这些发现，他们提出了泛素-蛋白酶体途径（UPP）受损在ALS-PDC发病机制中的潜在作用（1）。我们报告说，暴露于苏铁基因毒素甲基偶氮甲醇（MAM），苏铁苷元的ALS-PDC的病因已链接，持续扰动新生小鼠的脑UPP和改变的脑蛋白质的表达，也异常表达在ALSPDC。生命早期暴露于苏铁毒素（特别是MAM）是ALS-PDC的合理病因，转录诱变已被认为是一种可能的机制（4）。MAM是在日本苏铁棕榈（苏铁）中发现的偶氮葡萄糖苷（特别是苏铁素）的遗传毒性苷元，其与ALS相关的种子在本州岛纪伊半岛被用作传统药物和补品，该半岛是日本ALS-PDC以前的高发地（5）。在关岛，苏铁的种子以前被用来制作玉米粉圆饼状的扁平面包（tityas），面粉样品中含有残留浓度的苏铁蛋白（6），这与男性和女性的ALS和PD发病率密切相关（7）。MAM是一种强效诱变剂，可诱导细菌中的点突变和移码突变（8）以及大鼠神经元培养物中DNA损伤相关的tau蛋白表达增加（9）。对新生动物的实验研究表明，MAM（以醋酸盐形式给药）是一种强效的发育遗传毒素，可重现关岛和Kii ALS-PDC某些病例中发现的独特亚临床小脑和视网膜变化（10）。在出生后第3天（PND 3）单次皮下注射MAM醋酸盐（43 mg/kg）后1-19天检查小鼠小脑，发现DNA持续存在
To the Editor: In their recent JNEN paper (1) and associated articles (2, 3), Verheijen and colleagues demonstrate the presence of ubiquitin-Bþ1 (UBBþ1) protein associated with neurofibrillary tangles (tauopathy) in the brains of Japanese and Guamanians with amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS-PDC). They point out that UBBþ1 is a frameshift mutant of ubiquitin that is generated by molecular misreading, a type of transcriptional mutagenesis. UBBþ1 is a dose-dependent inhibitor of the ubiquitin-proteasome system, the major pathway for intracellular proteolysis. Positive immunostaining was also demonstrated for the ubiquitin-binding protein p62, ATG8, and ATG12, indicating abnormalities in the autophagy pathway. Based on these findings, they propose a potential role for impairment of the ubiquitin-proteasome pathway (UPP) in the pathogenesis of ALS-PDC (1). We report that exposure to the cycad genotoxin methylazoxymethanol (MAM), the aglycone of cycasin that has been linked etiologically to ALS-PDC, persistently perturbs the brain UPP of neonatal mice and changes the expression of brain proteins that are also abnormally expressed in ALSPDC. Early-life exposure to cycad toxins (notably MAM) is a plausible etiology for ALS-PDC, and transcriptional mutagenesis has been advanced as a possible mechanism (4). MAM is the genotoxic aglycone of azoxyglucosides (notably cycasin) found in the Japanese Sago Palm (Cycas revoluta), the ALS-associated seed of which was used as a traditional medicine and tonic in the Kii Peninsula of Honshu Island, the location of the former high incidence of ALS-PDC in Japan (5). On Guam, seed of Cycas micronesica was formerly used to prepare tortilla-like flatbread (tityas), flour samples for which contained residual concentrations of cycasin (6) that were strongly correlated with the incidence of ALS and PD among males and females (7). MAM is a potent mutagen that induces point mutations and frameshift mutations in bacteria (8) and DNA-damage-associated increased tau expression in rat neuronal cultures (9). Experimental studies with neonatal animals show that MAM (administered as the acetate) is a potent developmental genotoxin that reproduces the unique subclinical cerebellar and retinal changes found in some cases of Guam and Kii ALS-PDC (10). The cerebellum of mice examined 1–19 days following a single subcutaneous dose of MAM acetate (43mg/kg) administered on postnatal day (PND3) showed persistent DNA