The pathophysiology of neurodegenerative disease: Disturbing the balance between phase separation and irreversible aggregation.
The pathophysiology of neurodegenerative disease: Disturbing the balance between phase separation and irreversible aggregation.
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DOI：
10.1016/bs.pmbts.2020.04.021
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发表时间：
2020
影响因子：
--
通讯作者：
Wolozin B
中科院分区：
文献类型：
--
作者：
Webber CJ;Lei SE;Wolozin B
液-液相分离（LLPS）通过蛋白质的内在生物物理特性，在减少自由能和最大化熵的驱动下，将功能相关的蛋白质聚集在一起。LLPS的过程允许蛋白质形成结构，称为无膜细胞器。这些多样的、动态的细胞器活跃于细胞核、细胞质、线粒体和突触的广泛过程中，范围从细菌到植物再到真核生物。RNA和DNA存在促进LLPS的长链带电聚合物。因此，许多RNA结合蛋白（rbp）和DNA结合蛋白形成无膜细胞器。然而，高度浓缩的相分离状态也创造了促进不可逆蛋白质聚集体形成的条件。RNA和DNA结合蛋白的突变增加了不可逆聚集体的稳定性，也增加了不可逆聚集体的直接积累和来自无膜细胞器的积累。许多表现出疾病相关突变的rbp通过应激颗粒执行细胞质作用，应激颗粒是一种多效型RNA颗粒，可调节对应激的翻译反应。tau蛋白的磷酸化和寡聚化促进了其与rbp和核糖体蛋白的相互作用，影响了RNA的翻译；我们认为这是tau蛋白在压力下磷酸化的主要原因。持续的应激导致由rbp或tau组成的不可逆聚集体的积累，然后引起毒性并形成许多主要神经退行性疾病的标志性病理。这种病理生理最终导致多种形式的神经退行性疾病，其具体类型反映了不同聚集蛋白的时间和空间积累。
Liquid-liquid phase separation (LLPS) brings together functionally related proteins through the intrinsic biophysics of proteins in a process that is driven by reducing free energy and maximizing entropy. The process of LLPS allows proteins to form structures, termed membrane-less organelles. These diverse, dynamic organelles are active in a wide range of processes in the nucleus, cytoplasm, mitochondria and synapse, and ranging from bacteria to plants to eukaryotes. RNA and DNA present long chained charged polymers that promote LLPS. Consequently, many RNA binding proteins (RBPs) and DNA binding proteins form membrane-less organelles. However, the highly concentrated phase separated state creates conditions that also promote formation of irreversible protein aggregates. Mutations in RNA and DNA binding proteins that increase the stability of irreversible aggregates also increase the accumulation of irreversible aggregates directly and from membrane-less organelles. Many of the RBPs that exhibit disease-linked mutations carry out cytoplasmic actions through stress granules, which are a pleiotropic type of RNA granule that regulates the translational response to stress. Phosphorylation and oligomerization of tau facilitates its interactions with RBPs and ribosomal proteins, affecting RNA translation; we propose that this is a major reason that tau becomes phosphorylated with stress. Persistent stress leads to the accumulation of irreversible aggregates composed of RBPs or tau, which then cause toxicity and form many of the hallmark pathologies of major neurodegenerative diseases. This pathophysiology ultimately leads to multiple forms of neurodegenerative diseases, the specific type of which reflects the temporal and spatial accumulation of different aggregating proteins.
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影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
25
作者：
Chou CC;Zhang Y;Umoh ME;Vaughan SW;Lorenzini I;Liu F;Sayegh M;Donlin-Asp PG;Chen YH;Duong DM;Seyfried NT;Powers MA;Kukar T;Hales CM;Gearing M;Cairns NJ;Boylan KB;Dickson DW;Rademakers R;Zhang YJ;Petrucelli L;Sattler R;Zarnescu DC;Glass JD;Rossoll W
通讯作者：
Rossoll W
DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
16.6
作者：
Ambadipudi S;Biernat J;Riedel D;Mandelkow E;Zweckstetter M
通讯作者：
Zweckstetter M
DOI：
10.1073/pnas.1509317112
发表时间：
2015-09-22
影响因子：
11.1
作者：
Berry, Joel;Weber, Stephanie C.;Brangwynne, Clifford P.
通讯作者：
Brangwynne, Clifford P.