Alkbh8, or AlkB homolog 8, is a methyltransferase that modifies tRNAs by methylating the anticodon wobble uridine residue. It is involved in regulating selenoprotein translation through the modification of the wobble uridine (U34) in tRNA, and plays a role in maintaining neural function, redox homeostasis, and is associated with codon-biased translation in cancer [2,1,3]. Genetic models, such as knockout mice, have been crucial for studying its functions.

In Alkbh8-knockout (Albkh8-/-) mice, reduced 5-methoxycarbonylmethyluridine (mcm5U) levels were observed, leading to abnormal behaviors indicating central nervous system dysfunction, along with reduced brain weight and ischemic pathological changes [1]. Alkbh8-/-embryonic fibroblasts display elevated ROS levels, increased DNA and lipid damage [4]. In Drosophila, ALKBH8 null animals lack wobble uridine methylation, show reduced protein synthesis in the nervous system, ectopic synapse formation, and memory impairments [5].

In conclusion, Alkbh8 is essential for maintaining neural function, redox homeostasis, and normal synaptic development and memory. The Alkbh8 knockout mouse models have contributed significantly to understanding its role in neurological diseases, oxidative stress-related pathologies, and intellectual disability [1,4,5].

References:

1. Honda, Kohei, Hase, Hiroaki, Tanikawa, Sayaka, Nakagawa, Shinsaku, Tsujikawa, Kazutake. 2024. ALKBH8 contributes to neurological function through oxidative stress regulation. In PNAS nexus, 3, pgae115. doi:10.1093/pnasnexus/pgae115. https://pubmed.ncbi.nlm.nih.gov/38550277/

2. Maddirevula, Sateesh, Alameer, Seham, Ewida, Nour, Vågbø, Cathrine Broberg, Alkuraya, Fowzan S. 2021. Insight into ALKBH8-related intellectual developmental disability based on the first pathogenic missense variant. In Human genetics, 141, 209-215. doi:10.1007/s00439-021-02391-z. https://pubmed.ncbi.nlm.nih.gov/34757492/

3. Dedon, Peter C, Begley, Thomas J. 2022. Dysfunctional tRNA reprogramming and codon-biased translation in cancer. In Trends in molecular medicine, 28, 964-978. doi:10.1016/j.molmed.2022.09.007. https://pubmed.ncbi.nlm.nih.gov/36241532/

4. Endres, Lauren, Begley, Ulrike, Clark, Ryan, Dedon, Peter C, Begley, Thomas J. 2015. Alkbh8 Regulates Selenocysteine-Protein Expression to Protect against Reactive Oxygen Species Damage. In PloS one, 10, e0131335. doi:10.1371/journal.pone.0131335. https://pubmed.ncbi.nlm.nih.gov/26147969/

5. Madhwani, Kimberly R, Sayied, Shanzeh, Ogata, Carlson H, Fu, Dragony, O'Connor-Giles, Kate M. 2024. tRNA modification enzyme-dependent redox homeostasis regulates synapse formation and memory. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2317864121. doi:10.1073/pnas.2317864121. https://pubmed.ncbi.nlm.nih.gov/39495910/