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Advanced Neurology LLPS in neurodegenerative diseases

droplet-like nucleosomal TDP-43 nuclear bodies (NBs) [RIM-BP]) form active zones for neurotransmitters,
co-localize with nuclear speckles, and the formation of which are essential in synaptic transmission. However,
TDP-43 NBs in mammalian and Drosophila neurons the exact mechanism of active zone assembly remains
attenuates TDP-43-mediated cytotoxicity. In contrast, the unclear. Protein–protein interactions enable liprin-α to act
ALS-associated TDP-43-D169G mutant impairs lncRNA together with active zone scaffold proteins. Oligomerized
NEAT1-mediated LLPS, causing excessive cytoplasmic liprin-α mediates ELKS and RIM/RIM-BP LLPS
translocation of TDP-43 and assembling into stress through protein polyvalent interaction, and determines
granules (SGs). Dynamic impairment under prolonged compartmentalization of protein distribution, realizing the
stress promotes the accumulation of pTDP-43 cytoplasmic integrated function of active zones. 33
lesions. ALS/frontotemporal dementia (ALS/FTD)- Synaptic proteins crosslink synaptic vesicles and bind
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associated mutations S96del or G156E in FUS LCD alter the them to the cytoskeleton within the resting pre-synaptic
properties of LLPS droplets and increase the propensity for terminals. Synaptic proteins can aggregate synaptic vesicles
an irreversible fibrillar hydrogel state. Ribonucleoprotein at pre-synaptic terminals through an LLPS-mediated
(RNP) particle function is critical for intracellular mechanism. 34 Ca -activated calmodulin-dependent
2+
transport, RNA metabolism, and local protein synthesis. protein kinase (CaMK) II phosphorylates synaptic proteins,
The assembly of irreversible RNP granules containing reducing the interaction of synaptic proteins with synaptic
mutant FUS interferes with RNP granule function, which vesicles and the cytoskeleton, and facilitating the process
in turn leads to neurotoxicity. 20 of vesicle release. The purified synaptic proteins undergo

3. Signal transduction LLPS in vitro. Synaptic protein condensates can capture
liposomes and disperse by CaMKII phosphorylation.
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Synapses are the molecular devices for processing and Voltage-gated Ca channels (VGCCs) bind directly to RIM
2+
transmitting signals between neurons and represent the and RIM-BP through C-terminal tail mediation, and can
basic units of neural networks. Higher-level activities, be enriched into RIM and RIM-BP condensates. RIM and
such as learning and memory, are inextricably linked to RIM-BP aggregate VGCCs into nano- or microdomains
synaptic plasticity. Impaired synaptic plasticity is therefore on the lipid membrane bilayer through LLPS, and locate
closely related to neurodegenerative diseases. For example, the Ca channels and Ca sensors on the docking vesicles
2+
2+
abnormal synaptic plasticity is one of the causes of to achieve efficient and accurate synaptic transmission.
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Parkinson’s disease and Huntington’s disease. One of the LLPS at the synapse may be envisaged for RIM–RIM-BP–
pathological features of Alzheimer’s disease is the loss of VGCC aggregates in pre-synaptic active zones, which
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synapses, which is accompanied by cognitive decline. 26-28 will be a form of communication between membraneless
Synapses have very delicate and complex structures organelles and membrane-associated organelles.
and change their molecular composition and signal
transduction instantly in response to different stimuli, 3.2. Post-synaptic density
requiring rapid protein transport and spatiotemporal The post-synaptic density (PSD) is located beneath the
coordination of cells. LLPS mediates synaptic assembly post-synaptic membrane of each synapse. The function of
and participates in synaptic physiological functions, thus the PSD in receiving, amplifying, and storing pre-synaptic
actively participating in the regulation of synaptic plasticity cellular signals is essential for neuronal activity. The PSD
and local protein synthesis. 29-31 The biophysical properties consists of hundreds of concentrated proteins. The main
of LLPS indicate that they are sensitive to small changes components of PSD are scaffold proteins PSD-95, Shank3,
in the environment and proteins, and allow rapid material GKAP, and Homer. PSD is characterized by a dense protein
exchange with solvents. An increasing number of studies component bound to the dendritic spine cytoplasm on
have shown that synaptic structures contain various one side of the post-synaptic plasma membrane and
biological condensates, such as active zone condensate and exposed on the other side, which are dense subcellular
post-synaptic density. compartments not surrounded by lipid membranes.
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LLPS of synaptic scaffold protein and neurotransmitter
3.1. Pre-synaptic terminals receptor interactions may be involved in the formation
The function of the pre-synaptic active zone is crucial for of PSD assembly. 37,38 Dendritic spines and PSD are
rapid neurotransmitter release and well-regulated synaptic highly dynamic, and the volume of dendritic spines is
vesicle recycling. LLPS is involved in the functional closely related to synaptic strength. This corresponds
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regulation of pre-synaptic active zone proteins. Synaptic to the property of LLPS that the PSD condensate can
scaffold proteins in pre-synaptic terminals (e.g., liprin-α, be dynamically enlarged or contracted to facilitate the
Rab3 interacting molecule [RIM], and RIM binding protein addition or removal of new proteins.

Volume 4 Issue 1 (2025) 42 doi: 10.36922/an.4493