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.

液相-液相分离（LLPS）通过减少蛋白质的内在生物物理过程将功能相关的蛋白质聚集在一起，该过程由降低自由能和最大程度地提高熵来驱动。LLPS的过程允许蛋白质形成称为无膜细胞器的结构。这些多样的动态细胞器在细胞核，细胞质，线粒体和突触的广泛过程中活跃，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结合蛋白形成了无膜细胞器。然而，高度浓缩的相分离状态创造了也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，也直接增加了不可逆聚集体从无膜细胞器中的积累。表现出与疾病相关的突变的许多RBP通过应激颗粒执行细胞质作用，应激颗粒是多效型的RNA颗粒，可调节对应激的翻译反应。tau的磷酸化和寡聚化促进了它与RBP和核糖体蛋白的相互作用，影响RNA的翻译；我们认为这是tau因压力而被磷酸化的主要原因。持续的压力导致由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。