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Written by Sheng Nengyin, Ma Pengcheng
Responsible editor—，
Editor—Summer Leaf
The human brain contains about 10 billion neurons, which are connected to each other through synaptic structures to form a neural network for information exchange and integration, which is the material basis for
performing various physiological functions of the brain.
Its functional regulation disorder is one of the important causes of neuropsychiatric diseases, and it is also an important target for the intervention and treatment of
related diseases.
Glutamate is the main excitatory neurotransmitter in the brain, and the expression level of glutamate receptors corresponding to it at the synaptic site of neurons is an important determinant of
synaptic information transmission efficiency and neural network activity.
The expression localization and functional regulation of AMPA-type glutamate receptors in the postsynaptic membrane determine the intensity of excitatory synaptic transmission activity, and this process is neuronal
activity-dependent.
The transport regulation process of AMPA receptors in neurons determines their dynamic changes in the postsynaptic membrane, which is also a key prerequisite for synaptic plasticity (long-term enhancement of LTP and long-term inhibition of LTD) [1]
。 AMPA receptors are tetrameric complexes composed of different combinations of GluA1/2/3/4 subunits, and multiple protein post-translational modifications (phosphorylation, glycosylation, and palmitoylation) of these subunits are known to be involved in the regulation of postsynaptic membrane AMPA Dynamic transport process of receptors[2].
While ubiquitination-proteasome system-mediated regulation of protein stability plays an important role in synaptic transmission and plasticity[3], the molecular mechanism of regulation of AMPA receptor ubiquitination, And how it affects excitatory synaptic transmission activity is still poorly
understood.
At present, the AMPA receptor E3 ubiquitin ligase has been identified as Nedd4, Nedd4L, and APCCdh1 and RNF167, which are also involved in the regulation of excitatory synaptic transmission activity [4, 5], and mediate AMPA Receptor protein stability regulation disorders may also be closely related to the occurrence and development of related neurological diseases, such as epilepsy-related Nedd4L gene point mutations that affect the ubiquitination of GluA1 receptors and lead to neuronal overexcitation [5].
However, the role and molecular mechanism of AMPA receptor ubiquitination regulation in the regulation of excitatory synaptic function, and how this molecular regulation is intrinsically related to neurological diseases, need to be further studied
.
The team has long been concerned about the mechanism of action of E3 ubiquitin ligase RNF220 in the development of the central nervous system, and in recent years, systematic research work has found that it plays an important role in the development process of nerve cell fate determination and neural tube patterning [6-11
。 A recent genetic study of the disease reported that homozygous mutations of RNF220 (R363Q and R365Q) cause abnormal brain function, and several clinical symptoms are strongly associated with synaptic regulatory disorders, such as intellectual disability and epilepsy [12]
。 Although the previous research results of the research group also showed that the gene is also highly expressed in the adult cortex and hippocampus of mice, it is still unknown about the ubiquitinated substrate and biological function of RNF220 in mature neurons, especially whether the molecular regulation is involved in synaptic regulation and brain physiological function and pathological process
.
On September 30, 2022, Sheng Nengyin, researcher and Mao Bingyu, researcher of Kunming Institute of Zoology, Chinese Academy of Sciences, and Ding Yuqiang of Fudan University The professor's group collaborated to publish an online publication entitled "RNF220 is an E3 ubiquitin ligase for AMPA receptors to regulate synaptic transmission" in Science Advances.
article, answering the above scientific question
.
This study revealed the functional and molecular mechanisms
of RNF220 as a novel ubiquitinylated ligase of AMPA receptor in the regulation of synaptic transmission activity.
In order to elucidate the functional mechanism of RNF220 in mature neurons, the researchers crossed RNF220 fl/fl conditional knockout mice with Emx1-Cre tool mice for its main expression in the cortex and hippocampus in adult brains , to achieve specific knockout of RNF220 molecules in the forebrain region, found:
(1) In this mouse model, there were no abnormalities in the development and morphological structure of the cerebral cortex and hippocampus; However, electrophysiological experimental analysis found that the amplitude and frequency of AMPA receptor-mediated tiny excitatory synaptic current (mEPSC) and stimulatory excitatory synaptic current (eEPSC) were significantly enhanced, while LTP was enhanced over a long time Significantly weakened
capacity.
At the same time, the results of biochemical experimental analysis showed that the expression level of AMPA receptors in the postsynaptic dense body (PSD) increased significantly, while the expression of NMDAR and other key proteins of excitatory synapses did not change significantly (Figure 1A-C).
This finding suggests that the E3 ligase RNF220 is involved in regulating excitatory synaptic transmission and synaptic plasticity, and suggests that it
may play a role by modulating the protein stability of AMPA receptors.
.
(Source: Ma et al.
, Sci Adv, 2022).
(2) To test this hypothesis, the researchers further combined in vitro cells and cultured hippocampal brain slices and in vivo mouse models and found that the GluA1 and GluA2 receptors are RNF220 Direct substrate of ubiquitin ligase, and overexpression of RNF220 enzyme active mutants or RING domain-deletion structures does not affect AMPA receptor-mediated eEPSC It was shown that the enhancement of AMPA receptor-mediated eEPSC by RNF220 was dependent on its ubiquitination ligase activity.
Through ubiquitination analysis of AMPA receptor point mutations, the researchers found K823 and K868 in the intracellular terminal domain of GluA1 And the K825, K848, and K864 sites in the intracellular terminal domain of GluA2 are RNF220 Sites that mediate ubiquitinization
.
Further analysis showed that RNF220 was mutated when the underlying RNF220 ubiquitination site at the intracellular end of the GluA1 and GluA2 receptors was mutated Nor can it regulate the expression localization of these two receptors in the excitatory postsynaptic membrane (Figure 1D).
In addition, RNF220 is involved in the protein stability regulation mechanism of AMPA receptor and the transport and expression of
AMPA receptor in neuronal cell membranes.
(3) Neurobehavioral analysis related to learning and memory in the above mouse models showed that RNF220 molecules significantly reduced the short-term memory ability of mice, such as fear memory, new object recognition and social memory, after the loss of the forebrain, while the long-term memory level, such as water maze and fear memory, did not change significantly (Figure 1E).
(4) Molecular biochemical analysis found that two RNF220 pathogenic mutations R363Q and R365Q were found in disease genetics It will significantly weaken the interaction between RNF220 and AMPA receptor and the ubiquitination regulation process of the latter.
At the same time, the electrophysiological results also confirmed that these two pathogenic mutations caused RNF220 to lose its ability to regulate excitatory synaptic transmission activity.
And immunofluorescence experiments also proved that the two pathogenic mutations of RNF220 could not rescue the elevation of AMPA receptor localization in the neuronal membrane caused by its deletion (Figure 1F).
。
Figure 2 Work summary figure: RNF200 as a novel AMPA receptor ubiquitinylated linkase regulates synaptic activity and neurobehavior
(Source: Sheng Nengyin/Mao Bingyu/Ding Yuqiang's team)
This paper clarifies its mechanism of excitatory synaptic transmission and plasticity regulation and learning and memory function, and proposes the potential mechanism of RNF220 gene mutation leading to human intellectual disability and other neurological diseases, which enriches people's understanding of the stable regulation of synaptic protein in brain physiological function and related pathological processes, and provides an important theoretical basis for the diagnosis and treatment of related diseases (Figure).
2）
。 In this study, we focused on the regulation of synaptic-associated protein stability by RNF220, and it cannot be ruled out that RNF220's regulation of other target proteins is also involved in this physiological process
.
In addition, whether RNF220 plays an important role in other types of nerve cells in the brain needs to be further studied and confirmed; At the same time, the future analysis of gene knock-in mice carrying pathogenic mutations of RNF220 gene will help to further fully understand the mechanism of neurosystem-related diseases caused by RNF220 mutations, and provide animal model support
for the diagnosis and treatment of related diseases.
Original link: style="outline: 0px;color: rgb(172, 57, 255);font-size: 12px;">
Ma Pengcheng, associate researcher and doctoral student Wan Li and Li Yuwei, Kunming Institute of Zoology, Chinese Academy of Sciences, doctoral student of Tongji University He Chunhui is the co-first author of the paper; Prof.
Sheng Nengyin and Mao Bingyu, Kunming Institute of Zoology, Chinese Academy of Sciences, and Professor Ding Yuqiang of Fudan University are the co-corresponding authors
of the paper.
The research was supported by grants
from the National Natural Science Foundation of China, the Chinese Academy of Sciences, and the Department of Science and Technology of Yunnan Province.
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