R E S E A R C H @ H K U S T
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Led by Prof Zhang, team leader Dr
Menglong Zeng (then a PhD student
and now a postdoctoral fellow) and
other researchers leveraged such
experience – and hundreds of lab hours
spent in sample preparation to obtain the
high-quality specimens necessary for
rigorous characterization – to elucidate
the structural basis for the inter-
action between SynGAP and PSD-95.
The study showed the two protein
molecules could form an autonomously
assembled network structure, with
SynGAP forming a coiled-coil trimer
that can bind to multiple copies of
PSD-95. The researchers then deduced
and demonstrated that binding of the
two proteins induces the spontaneous
formation of stable “oil-like” droplets
through phase transition, a fundamental
physical chemistry phenomenon.
Excitingly, additional findings
indicated that the SynGAP/PSD-95
protein complex is crucial for SynGAP
stabilization in the postsynaptic
density and for stopping neurons from
overstimulation, or hyper-excitation.
Experiments involving mutated
SynGAP proteins, as found in
autistic patients’ brains, showed
that such proteins altered the
“oil-like” droplet formation, causing
the synapse to overreact. This
mechanism could explain why
the genetic disorder occurs.
The project was carried out in
collaboration with a research group
from Johns Hopkins University and
published in
Cell
in 2016.
“The identification of phase
transition
as
the
underlying
mechanism for synaptic protein
assembly formation could lead to a
paradigm shift in thinking in the
biology field overall, as it represents
a principle beyond those located in
traditional textbooks,” Prof Zhang said.
“Phase transition can explain why in a
test tube you can have the same protein
existing in two phases, one extremely
dense, the other diluted, and they can
exchange. This is what we observed in
living cells and systems but we didn’t
know how it happened. It may even be
how the evolution of life got underway.”
Over the years, research work by the
Zhang Lab has been awarded numerous
competitive grants, including the 2013
Areas of Excellence funding from the
Neurons communicate with each other via synapses.
Hong Kong Research Grants Council,
and led to a large number of publications
in leading journals, including
Cell
,
Science, Developmental Cell
, and
Proceedings of the National Academy
of Sciences
(
PNAS
).
The Zhang Lab is currently hard at
work to explore whether other synapses,
such as neuron-muscle connections,
use phase transition to build synaptic
protein assemblies. They are also
hoping that the findings may offer new
strategies for developing therapeutics
for treating neuropsychiatric disorders
such as autism, which currently have
no effective treatments. “When and
whether we are able to translate our
findings into real drugs lie a long way
forward from our discoveries. The
important thing is we now have a new
direction,” Prof Zhang said.
PSD-95
SynGAP
POSTSYNAPTIC
DENSITY
SynGAP CC-PBM
Phase transition of the
SynGAP/PSD-95 complex
3.0 min
Dendritic spine
Presynaptic terminal
3.5 min 4.0 min 6.0 min
SynGAP + PSD-95
PSD-95 PSG
The mice with mutations of SynGAP have hyper-excited synapses and
show autistic symptoms.
Prof Zhang suggested a model for phase transition-mediated formation of
the postsynaptic density (PSD). The phase transition occurs and “oil-like”
droplets form when PSD-95 and SynGAP bind together. The finding answers
an important neuroscience question of how PSD can form and stably exist.
Norm
ASD
Normal
synapse
Hyper-excited
synapse
