PDF(Pubmed)
Abstract：
A hypothesis of Alzheimer\'s disease etiology is proposed describing how cellular stress induces excessive polyamine synthesis and recycling which can disrupt nucleoli. Polyamines are essential in nucleolar functions, such as RNA folding and ribonucleoprotein assembly. Changes in the nucleolar pool of anionic RNA and cationic polyamines acting as counterions can cause significant nucleolar dynamics. Polyamine synthesis reduces S-adenosylmethionine which, at low levels, triggers tau phosphorylation. Also, polyamine recycling reduces acetyl-CoA needed for acetylcholine, which is low in Alzheimer\'s disease. Extraordinary nucleolar expansion and/or contraction can disrupt epigenetic control in peri-nucleolar chromatin, such as chromosome 14 with the presenilin-1 gene; chromosome 21 with the amyloid precursor protein gene; chromosome 17 with the tau gene; chromosome 19 with the APOE4 gene; and the inactive X chromosome (Xi; aka \"nucleolar satellite\") with normally silent spermine synthase (polyamine synthesis) and spermidine/spermine-N1-acetyltransferase (polyamine recycling) alleles. Chromosomes 17, 19 and the Xi have high concentrations of Alu elements which can be transcribed by RNA polymerase III if positioned nucleosomes are displaced from the Alu elements. A sudden flood of Alu RNA transcripts can competitively bind nucleolin which is usually bound to Alu sequences in structural RNAs that stabilize the nucleolar heterochromatic shell. This Alu competition leads to loss of nucleolar integrity with leaking of nucleolar polyamines that cause aggregation of phosphorylated tau. The hypothesis was developed with key word searches (e.g., PubMed) using relevant terms (e.g., Alzheimer\'s, lupus, nucleolin) based on a systems biology approach and exploring autoimmune disease tautology, gaining synergistic insights from other diseases.
摘要：
提出了阿尔茨海默病病因的假设，描述了细胞应激如何诱导过度的多胺合成和再循环，从而破坏核仁。多胺在核仁功能中至关重要，如RNA折叠和核糖核蛋白组装。阴离子RNA和阳离子多胺作为抗衡离子的核仁池的变化可引起明显的核仁动力学。多胺合成减少S-腺苷甲硫氨酸，在低水平，触发tau磷酸化。此外，多胺回收减少了乙酰胆碱所需的乙酰辅酶A，这是阿尔茨海默病的低。异常的核仁扩张和/或收缩会破坏核仁周围染色质的表观遗传控制，如14号染色体具有早老素-1基因;21号染色体具有淀粉样前体蛋白基因;17号染色体具有tau基因;19号染色体具有APOE4基因;以及无活性X染色体(Xi;又名“核仁卫星”),具有正常沉默的精胺合成酶(多胺合成)和亚精胺/精胺-N1-乙酰转移酶(多胺再循环)等位基因。染色体17、19和Xi具有高浓度的Alu元件，如果定位的核小体从Alu元件中置换出来，则可以通过RNA聚合酶III转录。AluRNA转录本的突然泛滥可以竞争性地结合核仁素，核仁素通常与结构RNA中的Alu序列结合，从而稳定核仁异色壳。这种Alu竞争导致核仁完整性的丧失，核仁多胺的泄漏导致磷酸化tau的聚集。该假设是通过关键字搜索开发的(例如，PubMed)使用相关术语(例如，老年痴呆症,狼疮,核仁素)基于系统生物学方法，探索自身免疫性疾病重言式，从其他疾病中获得协同见解。
