Recent studies have found that phase separation could promote the abnormal aggregation of α-synuclein ( α-syn), an important pathological manifestation of PDD. However, the pathogenesis of PDD remains unclear. So far, it is believed that the etiology and pathogenesis of PDD are related to a combination of factors such as age, aging, genetics, and the environment. These lesions do not evenly wave to all areas of the brain but gradually accumulate to a specific extent showing the neuronal synaptic connection network, namely striatum-substantia nigra, which makes patients have a motor and nonmotor disorders, affecting everyday life and even life safety. The characteristic pathology of PDD is amyloid plaque deposition, neurofibrillary tangles (NFT), and massive loss of neurons.
Dementia has become one of the significant public health problems in the world in recent years, with about 7.7 million new cases diagnosed every year, of which PDD accounts for a large part. The incidence rate of Parkinson’s disease (PD) has gradually increased with age, which has affected about 1% of the elderly over 60 years old. LLPS and phase transition (LLPT) of proteins and nucleic acids have become a new research direction in cell biology. Because of the occurrence of many diseases is closely related to the liquid-solid phase transition process of protein and lipid production, such as Parkinson’s disease dementia (PDD). Through kinetic and thermodynamic ways, they undergo the liquid-solid phase transition to produce a liquid condensate that can mature and solidify, forming a structure similar to amyloid fibrin, and reaching an irreversible and more stable state.
Specifically, the viscosity and rigidity of these dynamic droplets increase over time. Biological macromolecules can be condensed into membrane-free condensates like liquid through liquid-liquid phase separation (LLPS). Several research results present show that phase separation generally exists in proteins, lipids, and other substances and participates in physiological and pathological processes by changing the state of substances. In the early stage, phase separation or phase transition was applied as a physical and chemical concept to explain the separation of mixed liquids, which was extended as a biological concept to study the occurrence and development of diseases. Determining the significance of LLPS in neurodegenerative diseases such as PDD will stimulate interest in research into treatments based on interference with abnormal LLPS. Therefore, we believe that LLPS can serve as one of the means to explain the pathological mechanism of PDD. 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. 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. Studies have shown that the occurrence and development of neurodegenerative diseases such as PDD are closely related to the separation of abnormal phases. However, the links and mechanisms between these factors remain unclear. The interaction of iron accumulation with α-syn and tau was further explored as an essential pathological mechanism of PDD. The pathological features of PDD are represented by dopaminergic neuronal death and intracellular α-synuclein ( α-syn) aggregation.
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