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REVIEW article

Front. Mol. Neurosci.
Sec. Brain Disease Mechanisms
Volume 17 - 2024 | doi: 10.3389/fnmol.2024.1494218
This article is part of the Research Topic Proteostasis disruption in neurodegenerative disorders: Mechanisms and treatment strategies View all articles

Liquid-Liquid Phase Separation and Conformational Strains of α-Synuclein: Implications for Parkinson's Disease Pathogenesis

Provisionally accepted
Eva D. Ruiz-Ortega Eva D. Ruiz-Ortega *Anna Wilkaniec Anna Wilkaniec Agata Adamczyk Agata Adamczyk *
  • Department of Cellular Signalling, Mossakowski Medical Research Institute (PAS), Warszaw, Masovian, Poland

The final, formatted version of the article will be published soon.

    Parkinson's disease (PD) and other synucleinopathies are characterized by the aggregation and deposition of alpha-synuclein (α-syn) in brain cells, forming insoluble inclusions such as Lewy bodies (LBs) and Lewy neurites (LNs). The aggregation of α-syn is a complex process involving the structural conversion from its native random coil to well-defined secondary structures rich in βsheets, forming amyloid-like fibrils. Evidence suggests that intermediate species of α-syn aggregates formed during this conversion are responsible for cell death. However, the molecular events involved in α-syn aggregation and its relationship with disease onset and progression remain not fully elucidated. Additionally, the clinical and pathological heterogeneity observed in various synucleinopathies has been highlighted. Liquid-liquid phase separation (LLPS) and condensate formation have been proposed as alternative mechanisms that could underpin α-syn pathology and contribute to the heterogeneity seen in synucleinopathies. This review focuses on the role of the cellular environment in α-syn conformational rearrangement, which may lead to pathology and the existence of different α-syn conformational strains with varying toxicity patterns. The discussion will include cellular stress, abnormal LLPS formation, and the potential role of LLPS in α-syn pathology. Killinger et al., 2022). Whereas in MSA, the inclusions found in oligodendrocytes are called glial cell inclusions (GCIs) (Kramer and Schulz-Schaeffer, 2007).Identifying genetic defects related to the α-syn gene, such as mutations and copy number variations in families with hereditary disorders, reinforces its significance (SNCA gene: MedlinePlus Genetics, 2021). Consequently, it is well-established that α-syn is the central protein involved in the pathology of several neurodegenerative diseases, including PD and other synucleinopathies (Lee V.

    Keywords: Parkinson's disease1, Alpha-synuclein2, liquid-liquid phase separation3, protein aggregation4, conformational strains5, cellular stress6, mitochondria7

    Received: 10 Sep 2024; Accepted: 10 Oct 2024.

    Copyright: © 2024 Ruiz-Ortega, Wilkaniec and Adamczyk. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Eva D. Ruiz-Ortega, Department of Cellular Signalling, Mossakowski Medical Research Institute (PAS), Warszaw, 02-106, Masovian, Poland
    Agata Adamczyk, Department of Cellular Signalling, Mossakowski Medical Research Institute (PAS), Warszaw, 02-106, Masovian, Poland

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.