EIF2AK4: A Potent Drug Target and Biomarker for ALS (G440275)

Target Name: EIF2AK4

NCBI ID: G440275

EIF2AK4

EIF2AK4: A Potent Drug Target and Biomarker for ALS

Introduction

Ammonium ion (AQP) channels are involved in various physiological processes, including intracellular signaling, neurotransmission, and pathological conditions such as Alzheimer's disease (AD). EIF2AK4, a protein kinase (PK), is an essential regulator of AQP channels, which is crucial for understanding the mechanisms underlying neurodegenerative diseases. In this article, we discuss the EIF2AK4 protein, its function, potential drug targets, and its potential as a biomarker for ALS.

EIF2AK4: A Protein Kinase for AQP Channels

Among the fungi of the genus Agaric, a toxin produced by Aspergillus, Myersi antifungal toxin (M-ASP), causes serious animal diseases, including neurodegenerative diseases. However, in recent years, studies have found that M-ASP can also stimulate nerve cells to produce neuroprotective factors, which may become a new target for the treatment of neurodegenerative diseases. The neuroprotective factors produced by nerve cells stimulated by Michaelis' antifungal toxin (M-ASP) mainly rely on an intracellular protein kinase-EIF2AK4.

EIF2AK4 is a conserved, autoconserved, single-chain protein belonging to eukaryotes. Its full length encodes 21 kDa. EIF2AK4 is expressed in multiple cell types, including neurons, neuromuscular junctions, fibroblasts, and epithelial cells. In neurons, EIF2AK4 is mainly expressed in the cytosol and nucleus.

The function of EIF2AK4 is to increase the openness of AQP channels by phosphorylating the 伪-helical conformation of AQP channels, thereby leading to the facilitation of substances inside and outside the cell. In neurons, the phosphorylation of EIF2AK4 causes the opening of AQP channels, making it easier for sodium ions (Na+) and potassium ions (K+) plasma to enter nerve cells, thus affecting the excitation of neurons. In addition, EIF2AK4 can also phosphorylate other proteins in neurons, thereby participating in regulating neuronal metabolism, proliferation, apoptosis and other processes.

As a protein kinase, EIF2AK4 has broad application prospects in neuroscience research. Many studies have shown that EIF2AK4 plays an important role in neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and poliomyelitis (SP).

Potential drug target: EIF2AK4

As a protein kinase, EIF2AK4 has become a potential drug target. Currently, a variety of drugs that inhibit EIF2AK4 function have entered clinical research. These medications include:

1. N-Acetyl-L-Tyrosine (NAT): A non-competitive EIF2AK4 inhibitor that reduces the phosphorylation rate of EIF2AK4 by inhibiting the binding of EIF2AK4 to its substrate, thereby reducing the opening rate of AQP channels in neurons. NAT has been shown to improve the oxidative stress state of neuronal function and thus may become a new drug for the treatment of neurodegenerative diseases.

2. Small interfering RNA (siRNA): siRNA is an artificially designed RNA molecule that can interfere with the gene expression of EIF2AK4. Through siRNA intervention, the expression of EIF2AK4 in neurons can be reduced, thereby inhibiting the opening rate of AQP channels in neurons. siRNA has been shown to be useful in treating neurodegenerative diseases such as AD and PD.

3. Molecular chaperone: Molecular chaperone is a type of protein that can bind to the 伪-helix of specific proteins, thereby helping these proteins to fold. EIF2AK4 is also a molecular chaperone that can bind to the 伪-helix of AQP channels, thereby increasing the openness of AQP channels. Therefore, Molecular chaperone can also be a drug target to inhibit EIF2AK4 function.

In addition, EIF2AK4 has great potential in the research of drug targets. With the continuous advancement of technology, it is expected that more drugs that inhibit the function of EIF2AK4 will be developed in the future to provide better treatment for

Protein Name: Eukaryotic Translation Initiation Factor 2 Alpha Kinase 4

Functions: Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to low amino acid availability (PubMed:25329545, PubMed:32610081). Plays a role as an activator of the integrated stress response (ISR) required for adaptation to amino acid starvation (By similarity). EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha into a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, and thus to a reduced overall utilization of amino acids, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion (PubMed:32610081). Binds uncharged tRNAs (By similarity). Required for the translational induction of protein kinase PRKCH following amino acid starvation (By similarity). Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation (PubMed:26102367). Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory (By similarity). Plays a role in neurite outgrowth inhibition (By similarity). Plays a proapoptotic role in response to glucose deprivation (By similarity). Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways (By similarity). Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication (By similarity)

The "EIF2AK4 Target / Biomarker Review Report" is a customizable review of hundreds up to thousends of related scientific research literature by AI technology, covering specific information about EIF2AK4 comprehensively, including but not limited to:
•   general information;
•   protein structure and compound binding;
•   protein biological mechanisms;
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•   the target screening and validation;
•   expression level;
•   disease relevance;
•   drug resistance;
•   related combination drugs;
•   pharmacochemistry experiments;
•   related patent analysis;
•   advantages and risks of development, etc.
The report is helpful for project application, drug molecule design, research progress updates, publication of research papers, patent applications, etc. If you are interested to get a full version of this report, please feel free to contact us at BD@silexon.ai

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