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Advanced Neurology LLPS in neurodegenerative diseases

A number of specific protein–protein interactions accelerate droplet aging and alter RNP particle dynamics,
mediate the organization of the PSD, constituting such as FUS, TDP-43, and hnRNPA1. Many mutations
functional post-synapses. PSD-95 interacts with various occurring at the prion-like disorder regions of these proteins
proteins, such as the C terminus of transmembrane AMPA may alter their conformation. 19,20,44,45 These mutations may
receptor (AMPAR) regulatory protein (TARP). AMPARs eventually lead to amyloid aggregation by promoting
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are the major receptor group at excitatory synapses. protein interactions. 46,47 Disease-related mutations tend
TARPs are a family of auxiliary subunits of AMPARs to reduce droplet mobility and accelerate fibrosis of RBP
that are essential for ion channel transport and synaptic droplets, and even form irreversible pathological fibers.
transport. Stargazin (Stg) is the first TARP identified. Stg It has been shown that disease mutations in protein LCD
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promotes the formation of condensate from LLPS through generally promote phase separation and reduce droplet
the multivalent interaction of PDZ-binding motif and dynamics and that disruption of the physiological balance
arginine-rich motif with PSD-95. LLPS is necessary for of this process may lead to pathological behavior of
the efficient binding of AMPARs to synapses and may be a membraneless organelles associated with them. However,
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mechanism of AMPAR synaptic aggregation and capture. disease-associated mutations do not necessarily alter LLPS
Charge-neutralizing mutations in the TARP C-terminal kinetics, nor do all mutations accelerate the transformation
arginine-rich tail motif attenuate TARP aggregation with of droplets into proteopathic aggregates. 19,49
PSD-95, impairing TARP-mediated AMPAR synaptic
transmission in mouse hippocampal neurons. 36,41 LLPS is a critical step before RBP aggregation. Recent
studies have revealed that in addition to increased local
SynGAP is a GTPase-activating protein (GAP) that protein concentration in the cohesive phase, irreversible
is highly enriched in the dendritic spines of excitatory aggregation can be triggered during LLPS by the key
neurons. SynGAP catalyzes the conversion of small G factor of RBP conformational changes; for example, Tau
proteins from GTP-binding to GDP-binding form and is conformational changes may be a key factor for irreversible
an inhibitor of synaptic activity, with a profound impact aggregation of pathogenic mutants such as P301L and
on synaptic plasticity. Shortly after LTP induction, CaMKII P301S. Recent studies have also shown that RING-in-
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is activated, followed by the activation of small G proteins. between-RING-type E3 ligase TRIAD3A(RNF216) is an E3
However, its cellular mechanism remains unclear. The ubiquitin (Ub) ligase of the RING-in-between-RING (RBR)
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C-terminal domain of SynGAP-α1 contains a class I PDZ class, an important gene in neurodegenerative diseases,
ligand sequence, which can bind to PSD-95. SynGAP forms droplets and accumulates Tau protein in them for
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forms curly helix trimers that bind to multiple copies
of PSD-95, and this polyvalent interaction of SynGAP/ autophagic degradation. Animal studies have shown that
PSD-95 drives the formation of LLPS in vitro and in TRIAD3A reduces the accumulation of phosphorylated
living cells. Importantly, the formation of SynGAP/PSD- tau, and disease-associated mutations in TRIAD3A affect
95 condensates is critical for SynGAP stabilization in the tau protein homeostasis by causing glial cell proliferation
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PSD. This is essential to prevent neuronal overexcitation. and exacerbating pathologic tau accumulation and
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In vitro reconstruction reveals that after the addition of spreading. hnRNPA1 G304Nfs*3 mutation in prion-like
other PSD proteins (GluN2B, GKAP, Shank, and Homer), domain (PrLD) removes several effective spatial zippers,
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the physiological concentration of spontaneous LLPS in reduces PrLD multivalency and leads to reduced fibrosis
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SynGAP/PSD-95 becomes lower. and more rapid SG disassembly. hnRNPA2 tyrosine
to glutamate mutation reduces the probability of spatial
4. Gene stability zipper formation. Disease mutations D290V and P298L
may greatly reduce the probability of in vitro aggregation. 52
Many diseases, such as cancer or neurodegenerative
diseases, are caused by genetic or epigenetic changes that Mutations in RNA-binding proteins can also lead
lead to defects in the acquisition of functions or to the loss to loss of RNA-binding protein function or altered
of functions. cohesive properties by affecting protein-RNA binding.
For example, it is widely observed that TDP-43 cohesions
4.1. Gene mutation have apparently hollow cores in RNA-binding-defective
Defects in functional acquisition are likely to be associated mutants of TDP-43, such as the acetylation-mimicking
with condensates, as mutations in phase-separated proteins mutant TDP-43 K145Q,K192Q , and three-dimensional live-
can affect not only the protein itself but also many other cell imaging reveals that these droplets often merge into
proteins in the condensate, leading to changes in the overall larger droplets. Recent studies reveal through real-time
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properties of the condensate. Mutations in RNA-binding imaging of living animals that RNA binding defects and
protein (RBP) associated with neurodegenerative diseases post-translational modifications can lead to aberrant

Volume 4 Issue 1 (2025) 43 doi: 10.36922/an.4493