Eif2ak3, also known as the gene encoding protein kinase RNA-like endoplasmic reticulum kinase (PERK), is a key regulator in the unfolded protein response (UPR) and integrated stress response pathways. PERK is crucial for maintaining cellular proteostasis, especially in response to endoplasmic reticulum (ER) stress. When ER stress occurs, PERK phosphorylates eukaryotic initiation factor 2 alpha (eIF2α), which can lead to a series of downstream effects, modulating global protein synthesis and selective translation of certain transcription factors [4,5].

In genetic studies, rare variants in Eif2ak3 were found to be associated with an increased risk of Alzheimer's disease (AD) in Dutch patients, with the variant p.R240H being a main driver [1]. In a case of Wolcott-Rallison syndrome (WRS), a rare autosomal recessive disease, novel compound heterozygous mutations in Eif2ak3 were identified, establishing it as the pathogenic gene for WRS, which is characterized by neonatal diabetes, multiple epiphyseal dysphasia, and liver disease [2]. Additionally, the gut-microbe-derived metabolite trimethylamine N-oxide (TMAO) was shown to bind and activate PERK, promoting metabolic dysfunction [3]. In tauopathy models, modulation of PERK signaling showed that its activation prevented tau aggregation, while inhibition exacerbated it, suggesting that reduced PERK signaling may increase the risk of developing tauopathies [6]. Genetic variations in Eif2ak3, both coding and non-coding single-nucleotide variants (SNVs), were associated with neurocognitive impairment in people living with HIV, with coding SNVs affecting specific neurocognitive domains [7].

In conclusion, Eif2ak3, through its encoded protein PERK, is essential for cellular proteostasis and ER stress response. Model-based research, although not specifically from KO/CKO mouse models in the provided references, has revealed its significant roles in various disease conditions such as AD, WRS, metabolic diseases, tauopathies, and neurocognitive impairment in HIV-positive individuals. Understanding Eif2ak3 functions can potentially lead to new therapeutic strategies for these diseases.