Eif2ak3, also known as protein kinase RNA-like endoplasmic reticulum kinase (PERK), is a key regulator of the unfolded protein response (UPR) and integrated stress response. It phosphorylates eukaryotic initiation factor 2 alpha (eIF2α), which can globally reduce protein synthesis and selectively translate certain mRNAs, influencing various biological processes such as cell fate control [4,5].

Rare variants in Eif2ak3 may be associated with Alzheimer's disease (AD) risk, as gene-based burden analysis in a Dutch AD exome cohort showed a significant association, mainly driven by the p.R240H variant [1]. The Eif2ak3 gene is the pathogenic gene of Wolcott-Rallison syndrome (WRS), a rare autosomal recessive disease characterized by neonatal diabetes, multiple epiphyseal dysphasia, and liver disease [2]. Also, the gut-microbe-derived metabolite trimethylamine N-oxide (TMAO) binds to PERK, selectively activates the PERK branch of the UPR, and induces the transcription factor FoxO1, a key driver of metabolic disease [3]. In neurodegeneration, reduced PERK signaling correlated with increased tau neuropathology, and PERK pathway activation prevented tau aggregation [6]. In people living with HIV, genetic variations in Eif2ak3 are associated with neurocognitive impairment [7].

In conclusion, Eif2ak3 plays crucial roles in multiple biological processes and disease conditions. Its involvement in AD, WRS, metabolic diseases, neurodegeneration, and HIV-associated neurocognitive impairment highlights its significance. Understanding Eif2ak3 through these disease-related studies may provide insights into disease mechanisms and potential therapeutic targets.

References:

1. Wong, Tsz Hang, van der Lee, Sven J, van Rooij, Jeroen G J, Rademakers, Rosa, van Swieten, John C. 2018. EIF2AK3 variants in Dutch patients with Alzheimer's disease. In Neurobiology of aging, 73, 229.e11-229.e18. doi:10.1016/j.neurobiolaging.2018.08.016. https://pubmed.ncbi.nlm.nih.gov/30314817/

2. Zhang, Hui-Jie, Wang, Shi-Biao, Guo, Xiao-Feng, Lin, Ling, Hao, Yan. . [A case report of EIF2AK3-related Wolcott-Rallison syndrome and literature review]. In Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics, 21, 176-179. doi:. https://pubmed.ncbi.nlm.nih.gov/30782283/

3. Chen, Sifan, Henderson, Ayana, Petriello, Michael C, Morris, Andrew J, Biddinger, Sudha B. 2019. Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction. In Cell metabolism, 30, 1141-1151.e5. doi:10.1016/j.cmet.2019.08.021. https://pubmed.ncbi.nlm.nih.gov/31543404/

4. Hetz, Claudio, Papa, Feroz R. 2017. The Unfolded Protein Response and Cell Fate Control. In Molecular cell, 69, 169-181. doi:10.1016/j.molcel.2017.06.017. https://pubmed.ncbi.nlm.nih.gov/29107536/

5. Rozpedek, W, Pytel, D, Mucha, B, Diehl, J A, Majsterek, I. . The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress. In Current molecular medicine, 16, 533-44. doi:. https://pubmed.ncbi.nlm.nih.gov/27211800/

6. Park, Goonho, Xu, Ke, Chea, Leon, Han, Jaeseok, Lin, Jonathan H. 2022. Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation. In The Journal of biological chemistry, 299, 102821. doi:10.1016/j.jbc.2022.102821. https://pubmed.ncbi.nlm.nih.gov/36563857/

7. Akay-Espinoza, Cagla, Newton, Sarah E B, Dombroski, Beth A, Letendre, Scott L, Jordan-Sciutto, Kelly L. 2024. Genetic Variations in EIF2AK3 are Associated with Neurocognitive Impairment in People Living with HIV. In Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 19, 25. doi:10.1007/s11481-024-10125-x. https://pubmed.ncbi.nlm.nih.gov/38789639/