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Advanced Neurology LLPS in neurodegenerative diseases

condensate and compartmentalization alterations of material exchange. The condensates can quickly respond to
TDP-43 and that these altered condensation properties small changes in solution to assemble, disassemble, change
may be responsible for the change of liquid condensates material properties, etc. Small changes in temperature,
into solid aggregates. 54 pH, osmotic pressure, macromolecular crowding, and
Mutations in genes that do not encode RNA-binding other conditions in solution can significantly modulate
proteins are also involved in LLPS. Neuronal hypofunction LLPS. 5,63-65 For example, the C-terminal low-complexity
and decreased numbers in neurodegenerative diseases are domain of TDP-43 (TDP43-LCD) drives LLPS and is an
closely associated with decreased protein homeostasis. The important component of TDP-43 pathological inclusions
ubiquitin-proteasome system is an important component during neurodegeneration. TDP43-LCD LLPS is regulated
of protein quality control. Disease-associated mutations by solution pH and salt. TDP43-LCD spontaneously forms
can significantly affect cohesive assembly, droplet hydrogels and continues to form irreversible amyloid
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dynamics, and protein homeostasis. ALS-linked genes aggregates at low heparin concentrations.
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encoding the shuttle protein ubiquilin-2 (UBQLN2) with Post-translational modifications (PTM) such
missense mutations P497H, P497S, and P506T, among as phosphorylation, methylation, acetylation, and
others, impair droplet dynamics and show a propensity for guanylation can regulate cohesive assembly and
amyloid aggregation. 56,57 disassembly by affecting multivalent interactions.
Targeting PTM regulation may be a promising therapeutic
5. DNA damage response and DNA repair strategy for neurodegenerative diseases. For example,
DNA damage response and DNA repair defects are closely serine/threonine/tyrosine phosphorylation affects charge-
related to neurodegenerative diseases. Progeria syndrome, charge interactions. Arginine methylation alters volume,
for example, is caused by defects in DNA repair genes. charge distribution, hydrophobicity, and hydrogen
In addition, the accumulation of DNA damage has been bonding potential. 63,66-68 Tyrosine phosphorylation of the
observed in the brains of Alzheimer’s disease patients and ALS/FTD-associated protein hnRNPA2 glycine-rich LCD
in the spinal cord of ALS and FTD patients. 58,59 However, alters hnRNPA2 LLPS in vitro, blocks interactions with
it is unclear whether defects in DNA repair foci are a cause hnRNPF and ch-TOG, reduces aggregation in vitro, and
or a consequence of neurodegenerative disease. Recent downplays neurodegeneration in the Cryptobacterium
study has shown that the condensate formed by LLPS is hidradi model. 52
important for the DNA damage response. DNA repair Modulators such as RNA, proteins, metal ions, and
foci can be assembled by DNA repair proteins through small molecule compounds have been demonstrated
LLPS. Inhibition of poly (ADP-ribose) polymerase (PARP) to be extensively involved in LLPS regulation. 69-72 RNA
prevents the assembly of DNA repair lesions, leading has a high charge density and is an important regulator
to a neurodegenerative phenotype in motor neurons of condensates in the complex network of intracellular
of ALS patients, such as reduced organelle transport. interactions. RNA exerts synergistic or antagonistic effects
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In vitro reconstruction of PARP-1/PAR/DNA system, on RBP phase separation. Studies have elucidated that a
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FUS and PARP1 were observed to be located at the site of lower RNA: protein ratio promotes LLPS, while a higher
DNA double-strand breaks after induced DNA damage. ratio appears to inhibit LLPS. The human prion protein
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Mesoscale DNA repair foci can be organized by transient (PrP) is associated with infectious neurodegenerative
compartmentalization of LLPS and are rapidly dissolved diseases. A disease-associated stop codon mutation
after PAR glycosylation. In yeast, Rad52 DNA repair Y145Stop in PrP residue 145 results in a highly
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protein assembles into droplets through LLPS at DNA disordered N-terminal IDR. The material properties of
damage sites through the action of petite DNA damage- its spontaneously assembled condensates are regulated
inducible intranuclear microtubule filaments (DIMs) and by RNA. Low RNA concentrations promote LLPS, while
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fuses to repair center droplets. Larger droplets concentrate LLPS is eliminated at high RNA concentrations. A recent
tubulin and project short aster-like DIMs. With LLPS, study showed that the addition of RNA to α-Syn-PrP
the repair center and the longer DIM can be connected condensates weakens α-Syn-PrP interactions and disrupts
to mediate the movement of damaged DNA toward the ordered structural domains, preventing LLPS. These
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periphery of the nucleus for repair. 62 studies suggest that the critical buffering effect of RNA on
6. Condensate modulation aberrant phase transitions may be a potential mechanism
for inhibiting neurotoxicity. Complex interactions
Condensates or droplets are highly dynamic. The absence between RNA, PTM, and molecular crowding regulate
of a membrane envelope allows them to undergo rapid the formation and function of Tau condensates. 76,77 RNA

Volume 4 Issue 1 (2025) 44 doi: 10.36922/an.4493