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Advanced Neurology LLPS in neurodegenerative diseases

Biomolecular condensates bring a comprehensive the interface of cellular signaling and metabolism, even
perspective to developing new drugs and new minor shifts in their composition or physical properties
therapeutics, especially in the therapeutic area of may have profound implications for cellular function.
neurodegenerative diseases. Drug discovery strategies This underscores the importance of developing robust and
targeting LLPS condensates-modifying therapeutics reliable monitoring systems that can accurately capture
(c-mods) are becoming a hot research topic. With these subtle changes in real-time during therapeutic trials.
the help of protein neighborhood tagging, advanced While the therapeutic potential of c-mod strategies holds
microscopy techniques, and computational methods, great promise, the path forward involves addressing these
it is increasingly possible to explore the possibility challenges to realize the full potential of targeting LLPS in
of modulating the biological properties of specific disease management.
biomolecular condensates to discover drugs for
preventing or reversing disease. First, this approach 8. Summary
requires accurate primary phenotypic screening The newly discovered phenomenon of LLPS has gained
models to assess condensate changes during disease significant attention as it integrates insights from a
processes. Second, intervenable c-mods need to be diverse range of disciplines, including medical biology,
developed, a process that involves the specificity of this physics, chemistry, and engineering. This interdisciplinary
biological process. Ultimately, the target is detached or approach has fostered a rapidly expanding body of
retained in the condensate by the material properties research, revealing that LLPS plays a critical role in a
of the LLPS for functional intervention. Abnormal variety of cellular pathophysiological processes. LLPS
LLPS is often associated with protein aggregation in creates dynamic, membraneless droplets that can quickly
neurodegenerative diseases, and these aggregates may exchange components with the surrounding nuclear or
lead to cellular dysfunction or even cell death. By cytoplasmic environment. This ability for rapid assembly
altering the scaffold, composition, conformation, and and disassembly in response to minor intracellular changes
interaction landscape of condensates, their functions suggests that LLPS may serve as a key spatiotemporal
can be affected, thus providing new avenues for treating regulatory mechanism for cellular components and
related diseases. For example, altering the scaffold of biochemical reactions within the cell.
condensate can change the stability of the condensate,
and some small-molecule drugs have been shown to In the context of neurodegenerative diseases, current
interfere with structural interactions or protein-nucleic research predominantly focuses on factors such as aging,
acid interactions to affect condensate assembly. 90,91 neuroinflammation, oxidative stress, mitochondrial
dysfunction, brain metabolic imbalances, and impaired
The novelty and potential therapeutic efficacy of signal transduction pathways. Recent studies have
c-mods provide new directions for future drug discovery. uncovered that the multivalent interactions driving LLPS
During neurodegenerative pathologies, LLPS frequently are widespread within cells and profoundly influence
exhibits some paradigm shifts, suggesting the significance neuronal function on multiple fronts. 92-97 These include the
and feasibility of our potential intervention through regulation of gene expression, maintenance of chromatin
LLPS. However, this modification is also challenging, structure and genomic stability, signal transduction
as disease development involves complex genetic and processes, mitochondrial function, apoptosis, and the
environmental factors. For specific disease mutations, division of neural stem cells. These multifaceted roles
intervention by targeting aberrant LLPS processes is a position LLPS as a central player in maintaining neuronal
potentially powerful therapeutic tool, although it faces health and underscore its potential significance in the
both great opportunities and challenges. Condensates are pathogenesis of neurodegenerative diseases. Investigating
very sensitive to changes in the expression levels of their how LLPS impacts disease mechanisms could open up
components and regulators, as well as to environmental new, innovative pathways for regulating and intervening
changes, which poses challenges for phenotypic
monitoring. Effective phenotypic monitoring requires in disease progression through the modulation of
91
the maintenance of strict control over experimental and biomolecular condensates.
therapeutic conditions to ensure reproducibility of the However, our understanding of LLPS is still in its
observed effects. Any changes in condensate behavior, infancy. Due to the differences between in vivo and
including their kinetics, material properties, or the in vitro environments, criteria for the validation of LLPS
functional outcomes of therapeutic interventions, must in vivo have not been established, and the biological role
be carefully assessed to avoid inconsistent or misleading of LLPS in vivo has not yet been proven. There are also
results. Furthermore, because condensates function at questions about the mechanisms regulating biomolecular

Volume 4 Issue 1 (2025) 46 doi: 10.36922/an.4493