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Advanced Neurology

REVIEW ARTICLE
Liquid–liquid phase separation in

neurodegenerative diseases: An updated
understanding

Yiming Zhou 1,2,3 , Xinlu Chen 1,2,3 , Cihang Liu , Ying Wang , Tianjiao Xia *, and
4,5
2,3
1
1
Xiaoping Gu *
1 Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical Department, Nanjing
University, Nanjing, China
2 Medical School, Nanjing University, Nanjing, China
3 Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, China
4 Department of Biochemistry and Biophysics, Beijing Key Laboratory of Protein Post-translational
Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health
Science Center, Beijing, China
5 Center for Healthy Aging, Changzhi Medical College, Changzhi, China

Abstract
*Corresponding authors: Liquid–liquid phase separation (LLPS), once understood merely as a physicochemical
Tianjiao Xia
(tjxia@nju.edu.cn) phenomenon, has emerged over the past decade as a critical player in life
Xiaoping Gu processes. LLPS provides a novel framework for understanding the structure,
(xiaopinggu@nju.edu.cn) function, and spatiotemporal regulation of intracellular biomolecules. Through
Citation: Zhou Y, Chen X, LLPS, biomolecules within cells can spontaneously assemble into membraneless
Liu C, Wang Y, Xia T, Gu X. compartments, which allow precise regulation of biochemical reactions and
Liquid–liquid phase separation in
neurodegenerative diseases: An influence critical cellular processes such as signal transduction and gene
updated understanding. Adv Neurol. expression. Despite its recognized significance in basic biological research, the role
2025;4(1):40-52. of LLPS in human disease is still an area worthy of continued exploration. Currently,
doi: 10.36922/an.4493
the most studied disorders in relation to LLPS are neurodegenerative diseases and
Received: August 11, 2024 cancer. In neurodegenerative diseases, LLPS is closely linked to protein misfolding
Revised: September 24, 2024 and aggregation, processes that can lead to the formation of toxic assemblies,
ultimately causing neuronal damage and death. In cancer, aberrant LLPS may
Accepted: November 13, 2024
contribute to the dysregulation of signaling pathways, promoting uncontrolled
Published Online: December 16, cell proliferation and metastasis. This review highlights recent advances regarding
2024 the role of LLPS in the pathogenesis of neurodegenerative diseases, discussing
Copyright: © 2024 Author(s). its function in these pathological conditions and proposing directions for future
This is an Open-Access article research. As research progresses, the potential role of LLPS in other human diseases
distributed under the terms of the
Creative Commons Attribution will likely be uncovered, offering new avenues for diagnosis and therapy. Therefore,
License, permitting distribution, further investigation into the mechanisms of LLPS and its involvement in disease
and reproduction in any medium, pathology will be crucial for advancing our understanding of human health and
provided the original work is
properly cited. disease.
Publisher’s Note: AccScience
Publishing remains neutral with Keywords: Liquid–liquid phase separation; Neurodegenerative diseases; Protein
regard to jurisdictional claims in
published maps and institutional aggregation; Signal transduction; Gene mutation
affiliations.

Volume 4 Issue 1 (2025) 40 doi: 10.36922/an.4493