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.

The Role of Liquid‒Liquid Phase Separation in the Accumulation of Pathological Proteins: New Perspectives on the Mechanism of Neurodegenerative Diseases

“…α-Syn aggregation is also significantly influenced by metal ions. The pathogenesis of PD is closely related to iron metabolism [133]. Aggregation can be induced in iron-treated cells, probably because the accumulation of iron increases oxidative stress and further leads to lipid peroxidation [134,135].…”

Liquid–liquid phase separation in diseases

“…High concentrations of α‐synuclein trigger the process of LLPS and the formation of amyloid hydrogels containing oligomeric and fibrillar material 171,172 . Unstructured proteins of α‐synuclein form partially folded intermediates, then oligomerize and protofibrillate, ultimately giving rise to amyloids 173,174 . Furthermore, it has been shown that abnormally aggregated α‐synuclein molecules induce normal molecular misfolding to form polymers and are taken up by neurons, leading to neurodegenerative alternations 175 .…”

“…171,172 Unstructured proteins of α-synuclein form partially folded intermediates, then oligomerize and protofibrillate, ultimately giving rise to amyloids. 173,174 Furthermore, it has been shown that abnormally aggregated α-synuclein molecules induce normal molecular misfolding to form polymers and are taken up by neurons, leading to neurodegenerative alternations. 175 α-Synuclein aggregates are also closely related to mitochondrial autophagy.…”

Liquid-liquid phase separation regulates alpha-synuclein aggregate and mitophagy in Parkinson’s disease

“…Occurrence of α-syn LLPS α-syn misfolding and aggregate is a key target for PD treatment. Therefore, observing the role of α-syn LLPS in aggregate is crucial for us to clarify the pathogenesis of PD further (Giampa et al, 2021;Gadhe et al, 2022;Li et al, 2022). α-syn is a naturally unfolded protein consisting of 140 amino acids, which is abundantly present in presynaptic nerve endings, and consists of three structural domains: a positively charged amphiphilic N-terminal domain (residues 1-60), which interacts with the membrane; a hydrophobic non-amyloid beta component (NAC) domain (residues 61-95), which is involved in fiber formation and aggregate; and a negatively charged acidic C-terminal domain (residues 96-140), associated with α-syn nuclear localization and involved in the interaction of α-syn with metal ions, ligands and other proteins (Uversky and Eliezer, 2009;Poudyal et al, 2022).…”