Examining the Role of a Functional Deficiency of Iron in Lysosomal Storage Disorders with Translational Relevance to Alzheimer's Disease.
Examining the Role of a Functional Deficiency of Iron in Lysosomal Storage Disorders with Translational Relevance to Alzheimer's Disease.
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作者：
最近发表的针对阿尔茨海默氏症的杜鹃花假说认为，铁会被隔离，导致功能性铁缺乏，从而导致神经退化。铁的隔离可通过以下方式发生：铁与蛋白质聚集体结合，如淀粉样蛋白β和tau，富铁结构不再循环(例如，由于吞铁蛋白被破坏和有丝分裂作用受损)，以及减少铁从溶酶体到细胞质的输送。用于生化反应的铁的可获得性降低会导致细胞对获得额外的铁做出反应，导致受影响大脑区域的总铁水平上升。随着不可用铁含量的增加，可用铁的水平会下降，直到最终无法满足细胞的需求，从而导致功能性缺铁。正常情况下，溶酶体通过促进铁向胞浆的输送(例如，铁-转铁蛋白-转铁蛋白受体复合体内吞之后)和铁的细胞循环，在细胞铁稳态中发挥着不可或缺的作用。在溶酶体储存障碍期间，酶缺乏会导致未消化的底物积累，导致致病事件的后遗症，其中可能包括细胞铁代谢紊乱。因此，铁的功能性缺乏可能是几种溶酶体储存疾病和阿尔茨海默病的致病机制之一。
The recently presented Azalea Hypothesis for Alzheimer’s disease asserts that iron becomes sequestered, leading to a functional iron deficiency that contributes to neurodegeneration. Iron sequestration can occur by iron being bound to protein aggregates, such as amyloid β and tau, iron-rich structures not undergoing recycling (e.g., due to disrupted ferritinophagy and impaired mitophagy), and diminished delivery of iron from the lysosome to the cytosol. Reduced iron availability for biochemical reactions causes cells to respond to acquire additional iron, resulting in an elevation in the total iron level within affected brain regions. As the amount of unavailable iron increases, the level of available iron decreases until eventually it is unable to meet cellular demands, which leads to a functional iron deficiency. Normally, the lysosome plays an integral role in cellular iron homeostasis by facilitating both the delivery of iron to the cytosol (e.g., after endocytosis of the iron–transferrin–transferrin receptor complex) and the cellular recycling of iron. During a lysosomal storage disorder, an enzyme deficiency causes undigested substrates to accumulate, causing a sequelae of pathogenic events that may include cellular iron dyshomeostasis. Thus, a functional deficiency of iron may be a pathogenic mechanism occurring within several lysosomal storage diseases and Alzheimer’s disease.
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影响因子：
5
作者：
Bach, G;Chen, CS;Pagano, RE
通讯作者：
Pagano, RE
影响因子：
7.4
作者：
Camarena V;Huff TC;Wang G
通讯作者：
Wang G
DOI：
10.1016/j.bbrc.2011.06.135
发表时间：
2011-07-22
影响因子：
3.1
作者：
Bader, Benedikt;Nuebling, Georg;Giese, Armin
通讯作者：
Giese, Armin
影响因子：
30.8
作者：
Chang D;Nalls MA;Hallgrímsdóttir IB;Hunkapiller J;van der Brug M;Cai F;International Parkinson's Disease Genomics Consortium;23andMe Research Team;Kerchner GA;Ayalon G;Bingol B;Sheng M;Hinds D;Behrens TW;Singleton AB;Bhangale TR;Graham RR
通讯作者：
Graham RR
影响因子：
12.7
作者：
Castellani, RJ;Siedlak, SL;Smith, MA
通讯作者：
Smith, MA