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Synaptic ES is an emerging mechanism for health and disease
Membrane proteins play an essential role in health and disease; Therefore, their functions must be strictly regulated. One of the mechanisms regulating the properties of membrane proteins isEctodominium(see glossary) Detachment (ES), a process by which a protease cleaves the extracellular portion of transmembrane and glycosylphosphatidylinositol (GPI)-anchored proteins within 10 to 35 amino acids of the transmembrane region [1]. In some cases, an intramembrane protease can further cleave the protein
Synaptic ES is catalyzed by sheddases
Accumulating evidence suggests that many synaptically localized membrane proteins undergo ES (Figure 1B-D). This is supported by work focusing on individual proteins such as neuroligins (NLGN) and neurexins (NRXN) [6, 9, 10, 11] but also by global analyzes of the neuronal shell dome [2, 12, 13, 14]. . ES is catalyzed by proteases, also known asgoess that cleave their targets on the extracellular side near the membrane. matrix metalloproteases (MMPs), 'A-disintegrin and
Major synaptic proteins pass through ES
Several synaptic proteins have been shown to traverse ES. Below we discuss some of the better known examples (Table 1).
APP is a single-pass transmembrane protein abundant in synapses. The inappropriate proteolytic cleavage is a symbolic example of ES contributing to brain dysfunction. The amyloidogenic pathway is mediated by BACE1 activity followed by γ-secretase which produces the neurotoxic amyloid-β (Aβ). Processing of APP by antiamyloidogenic α-secretases (e.g., ADAM10) followed by
Physiological functions of synaptic ES
Many of the physiological functions of ES are just beginning to be discovered, and the function of most of the secreted ectodomains is currently unknown. However, several biological functions for synaptic ES can already be distinguished.
Global analyzes of neuronal SE and CSF
While most reports focus on ES of single proteins, an increasing number of studies around the world have focused on the shell dome, made possible by recent advances in proteomics. These studies typically include analysis of conditioned media from cultured neurons, sometimes followed by validation in mice. They led to the identification of new substrates for known sheddases such as BACE1 or ADAM10 [2,12], but also to new biological functions of ES [20]. Various analysis methods have been developed
Effects of synaptic ES on neuropsychiatric disorders
Altered ES, including synaptic proteins, are involved in CNS disorders. This suggests that the broader role of synaptic ectodomains in pathogenic processes or as biomarkers remains to be explored. The best studied example of deleterious ES is the cleavage of amyloidogenic APP in AD. However, ES has also been associated with other pathologies, such as glioma proliferation [11] or microglial cell activation [75]. As explained below, both global proteomic SE analyzes and surveys are performed
Caveat when studying the synaptic sheddome
There are several important caveats to studies of the synaptic shell dome. In experimental models, both spliced ectodomains and full-length membrane-bound proteins could bind to the same endogenous targets. In addition, competition from exogenous ectodomains with endogenous binding to their targets can be a confounding factor.
There are also certain caveats to mass spectrometric analysis. In mass spectrometry, due to the low number of peptides, some proteins may be missed and the results may be affected
Closing remarks and future prospects
Originally thought to be a mechanism that shut down the function of membrane proteins, ES is now believed to be an important post-translational mechanism regulating cell biology; This is supported by its role in the pathogenesis of diseases such as cancer and AD. Slingshot synaptic ectodomains develop into neuronal modulators that interact with classical neurotransmitters and neuromodulators. They have the potential to exert autocrine and/or paracrine effects as they can diffuse away from the body.
expression of gratitude
This work was funded by the National Institutes of Health (NIH) scholarshipNS100785(a PP).
Declaration of Interest
The authors declare that they have no competing financial interests.
word list
- Ectodominium
- the extracellular portion of a transmembrane domain or GPI-anchored protein. It can be part of the whole protein or be soluble and break down.
- Secret
- all proteins present in the extracellular milieu of a given biological sample (including secreted and released proteins).
- barn
- Protease that catalyzes the cleavage and detachment of ectodomains from membrane proteins.
- scale dome
- Subset of proteins in the secretome that traverse ES and therefore initially possess at least one transmembrane
Quoted by (1)
CCR5 deficiency normalizes TIMP levels, working memory and gamma swing performance in APOE4-specific surrogate mice
2023, Neurobiology of disease
IsAPOE4The allele dose-dependently increases the risk of Alzheimer's disease (AD) and is also associated with cognitive decline in older controls without dementia. In murine mice targeting gene replacement (TR).APOEwith humanAPOE3OAPOE4The latter show reduced neuronal dendritic complexity and impaired learning.APOE4TR mice also show decreased gamma oscillation performance, a population neuronal activity important for learning and memory. Published work has shown that the brain's extracellular matrix (ECM) can reduce neuroplasticity and gamma power, while ECM attenuation can improve this endpoint. In the current study, we examined human cerebrospinal fluid (CSF) samplesAPOE3JAPOE4individuals and brain lysatesAPOE3JAPOE4TR mice to levels of ECM effectors that can increase matrix deposition and limit neuroplasticity. We found that CCL5, a molecule associated with ECM deposition in liver and kidney, is elevated in CSF samplesAPOE4Individuals also have elevated levels of tissue inhibitors of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymesAPOE4Liquor supernatants and astrocytes, brain lysatesAPOE4TR mice. It is important to note that compared toAPOE4/Wildtype heterozygoot,APOE4/CCR5Knockout heterozygotes show decreased TIMP levels and increased EEG gamma output. The latter also show an improvement in learning and memory, suggesting that the CCR5/CCL5 axis could be a therapeutic targetAPOE4individuals
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