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Advanced Neurology LLPS in neurodegenerative diseases

1. Introduction 2. Protein aggregation

Liquid–liquid phase separation (LLPS) is a ubiquitous Irreversible protein aggregates are an important
phenomenon in biological system that drives the formation pathological feature of neurodegenerative diseases.
of membraneless compartments through the phase Through phase separation, biomolecules can be reversibly
separation of biomolecules such as proteins, nucleic acids, separated from the solution into a dense and dilute
and polysaccharides like glycogen. These compartments phase. The material properties of droplets assembled by
often referred to as condensates, arise from multivalent, LLPS evolve over time. Usually, droplets “age” over time,
weak, and transient interactions between macromolecules, characterized by a decrease in droplet dynamics, gelation,
5-7
including protein-protein, protein-RNA, and RNA-RNA or vitrification. There are multiple lines of evidence that
interactions. LLPS is particularly enriched in intrinsically aging can transform dynamically reversible droplets into
8,9
disordered regions (IDRs) or low-complexity domains irreversible solid amyloid fibrils. The physicochemical
(LCDs) of proteins, which lack a stable secondary or characteristics of LLPS are highly suggestive that it could
tertiary structure, making them highly flexible and prone act as a key link in the pathophysiological process of
to phase separation. These regions enable interactions such protein aggregation. An increasing number of studies
as π–π stacking, dipole–dipole interactions, cation–anion have demonstrated that pathological marker proteins for
interactions, and π–cation interactions, which collectively neurodegeneration, such as 43 kDa TARDNA binding
12
facilitate the reversible formation of liquid-like droplets. 1,2 protein (TDP-43), 10,11 fused in sarcoma (FUS), Tau, 13,14
16
15
Aβ, Huntingtin and α-synuclein (α-Syn), 17,18 share
LLPS plays important roles in neuronal signaling,
regulation of transcription and translation, ribosome certain similarities. LLPS is found to be a critical stage
Through LLPS, the local
before their aggregation.
5,10-13,17,19
biogenesis, oxidative stress, and other physiological concentration and volume crowding of biomolecules
functions of the cell. Neuronal degeneration and such as proteins and RNA within the condensate phase
death are characteristic features of neurodegenerative is significantly increased, which greatly increases the
diseases. Although the pathogenesis of different types of probability of nucleation and the risk of fibrillar aggregate
neurodegenerative diseases varies, a growing number of formation. Moreover, neurodegenerative pathological
studies indicate that LLPS plays a key role in the disease mechanisms such as disease-related mutations, stress, and
process. In neurodegenerative diseases, such as Alzheimer’s decreased proteostasis can also significantly affect phase
disease, Parkinson’s disease, and amyotrophic lateral separation and abnormal phase transition dynamics,
sclerosis (ALS), LLPS has been increasingly implicated which can have an impact on neuronal dysfunction and
as a key player in pathological protein aggregation and neurotoxicity. 12,20-24 For example, LLPS-mediated reversible
cellular dysfunction. Proteins that normally undergo LLPS
to form functional, dynamic condensates can transition
into aberrant solid-like aggregates under pathological
conditions. This transition is driven by mutations, post-
translational modifications, or environmental stress,
leading to the formation of amyloid fibrils or toxic protein
aggregates characteristic of neurodegenerative disorders. 1,3,4
The development of neurodegenerative diseases from
the perspective of LLPS has become an important research
topic. LLPS is believed to regulate the spatiotemporal
organization of signaling pathways and gene expression
in neurons and its dysregulation can contribute to disease
pathogenesis. Understanding how LLPS influences
signal transduction, gene stability, and condensate
modulation could provide new therapeutic targets for
preventing or reversing the aggregation of disease-related
proteins. This review aims to delve into these key areas –
protein aggregation, signal transduction, gene stability,
and condensate modulation – and explore how LLPS
contributes to both normal cellular function and disease
states, providing a comprehensive overview of the emerging Figure 1. Updated understanding of LLPS in neurodegenerative diseases
role of LLPS in neurodegenerative diseases (Figure 1). Abbreviation: LLPS: Liquid-liquid phase separation.

Volume 4 Issue 1 (2025) 41 doi: 10.36922/an.4493