中国博后一作Cell论文：在相分离中发生相分离，是渐冻症及痴呆症等疾病的关键致病机制

Core Viewpoint - The study reveals that TDP-43 protein undergoes intra-condensate demixing within stress granules, leading to pathological aggregation, which is a key mechanism in neurodegenerative diseases like ALS and FTD [2][14][16] Group 1: Mechanism of TDP-43 Aggregation - TDP-43 aggregation occurs through two critical steps: exceeding a concentration threshold and oxidative stress, resulting in intra-condensate demixing [2][9] - The aggregation process is characterized by a fivefold increase in TDP-43 concentration within stress granules, alongside oxidative modifications that expose vulnerable cysteine residues [10][14] - The study identifies that the C-terminal domain (CTD) structural changes and the interaction of hydrophobic regions drive TDP-43 separation and liquid-to-solid phase transition [5][10][14] Group 2: Implications for Neurodegenerative Diseases - TDP-43 mislocalization and aggregation are common features in approximately 97% of ALS cases and 45% of FTD cases, indicating a widespread pathological mechanism [4][14] - The findings suggest that stress granules may act as "crucibles" for TDP-43 aggregation, providing new insights into the pathogenesis of various neurodegenerative diseases [16] - The research highlights the potential therapeutic value of targeting the intra-condensate demixing process to prevent TDP-43 aggregation in motor neurons [12][16]