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Advanced Neurology LLPS in neurodegenerative diseases

can bind competitively to tau. Studies have demonstrated a clear boundary between the phases, impacting the way
that the tau: RNA ratio regulates the formation of protein condensates interact with other cellular structures. For
droplets from tau and RNA, which is a reversible and instance, interfacial tension can affect the merging of
sensitive process. 78 droplets or their interactions with membrane-bound
organelles. 84,85 While the redox state may affect the
PARP has also been proven to be a driver of
neurodegenerative diseases. PARP can synthesize the RNA- activity and interaction of proteins in the condensate and
interactions, the occurrence of oxidative stress, which is
like polymer poly (ADP-ribose) (PAR) through NAD . common in neurodegenerative diseases, impacts phasic
+
PARs have been found to be enriched in condensates. behavior. The properties of in vivo condensates vary
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A recent study revealed that PAR length determines the widely and are affected by the surrounding environment.
threshold and physical properties of protein condensates. The state of the condensate is constantly changing. In
When the PAR chain length is greater than 8 units, the neurodegenerative diseases, LLPS droplets can transition
extent of LLPS increases with increasing chain length. to a more solid state over time or due to mutations.
Moreover, a concentration three orders of magnitude Therefore, it is important to investigate whether it is
below the concentration of RNA-induced condensation possible to reverse this process by altering the material
(1 μM) triggers FUS condensation. 14-3-3ζ is an isoform properties of the condensate. Several theoretical models
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of the 14-3-3 protein family. There is growing evidence describe and predict LLPS, but these need to be supported
that 14-3-3 proteins are involved in Alzheimer’s disease by empirical evidence. 87
pathology. A recent study has revealed a modulatory role
of 14-3-3ζ on LLPS. 14-3-3ζ promotes tau LLPS through Condensates in cells have various functions, such
electrostatic and hydrophobic interactions between the as regulating transcription, signaling, and maintaining
proline-rich domain and the microtubule-binding domain protein quality. Abnormalities in condensates are linked
of tau, whereas the interaction between the disordered to a wide range of diseases. Therefore, new therapeutic
C-terminal tail of 14-3-3ζ and the N-terminal domain of approaches can be developed by altering the properties
tau negatively regulates tau LLPS. 80 of condensates. For instance, using small molecule drugs
or other biomolecules to control the formation and
7. Biophysical and chemical dissolution of condensates can impact the progression of
characterization of LLPS condensate a disease. This method has the potential to precisely target
disease-related biomolecular condensates without affecting
Biophysical and chemical properties of LLPS condensates, similar condensates in the cell, thus reducing potential side
such as viscosity, polarity/solvation, interfacial tension, effects. A recent study utilized optogenetics to manipulate
and redox state, are critical to understanding their function the material properties of transcription factor condensates,
within the cell and are increasingly being discussed in discovering that the material properties of condensates
the context of disease relevance. Viscosity is a defining influence their ability to activate target promoters.
feature of LLPS condensates. These condensates can range Transcription factors in relatively liquid condensates were
from highly viscous, gel-like states to more dynamic found to be associated with increased gene expression,
liquid states. This property is crucial as it influences the while those in relatively solid condensates had the opposite
condensates’ ability to regulate intracellular reactions, effect. The strength of intermolecular interactions in
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allowing selective retention or diffusion of molecules. LLPS is intricately linked to the thermodynamic stability
The dynamic behavior of condensates also enables rapid and viscoelasticity of the condensate. Researchers have
assembly or disassembly in response to environmental demonstrated that by manipulating the phase behavior
changes, which is crucial in processes such as stress of light-activated assembly, they can precisely tune the
response and gene regulation. Polarity and solvation composition and material properties of the condensate.
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properties determine the affinity of the condensate for When the condensate solidifies, it temporarily inhibits the
different molecules and affect the accumulation and release translational activity of mRNA. In addition, modulation
of molecules in the condensate, allowing the molecules to of condensate-based translational repression in neuronal
form transient, reversible interactions that lead to phase cells can effectively influence downstream cellular activity.
separation. Polar and hydrophobic interactions govern For example, isolating β-actin mRNA from neurons
the assembly of biomolecules within the condensate. 82,83 inhibits spine enlargement during chemically-induced
The formation of condensates is influenced by interfacial prolonged enhancement. This evidence emphasizes how
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tension, which results from variations in solubility and the material properties of condensates modulate function
molecular composition between the condensed and and the potential intervenability of such modulatory
surrounding phases. High interfacial tension establishes mechanisms.

Volume 4 Issue 1 (2025) 45 doi: 10.36922/an.4493