Liquid-Liquid Phase Separation Promotes Protein Aggregation and Its Implications in Ferroptosis in Parkinson's Disease Dementia.

Abstract

The pathological features of PDD are represented by dopaminergic neuronal death and intracellular α-synuclein (α-syn) aggregation. The interaction of iron accumulation with α-syn and tau was further explored as an essential pathological mechanism of PDD. However, the links and mechanisms between these factors remain unclear. Studies have shown that the occurrence and development of neurodegenerative diseases such as PDD are closely related to the separation of abnormal phases. Substances such as proteins can form droplets through liquid-liquid phase separation (LLPS) under normal physiological conditions and even undergo further liquid-solid phase transitions to form solid aggregates under disease or regulatory disorders, leading to pathological phenomena. By analyzing the existing literature, we propose that LLPS is the crucial mechanism causing abnormal accumulation of α-syn, tau, and other proteins in PDD, and its interaction with iron metabolism disorder is the key factor driving ferroptosis in PDD. Therefore, we believe that LLPS can serve as one of the means to explain the pathological mechanism of PDD. Determining the significance of LLPS in neurodegenerative diseases such as PDD will stimulate interest in research into treatments based on interference with abnormal LLPS.