Alkbh8, or AlkB homolog 8, is a methyltransferase involved in tRNA modification. It methylates the anticodon wobble uridine residue of tRNAs, regulating selenoprotein translation [2]. This process is essential for proper protein translation and is linked to several biological functions and disease pathophysiologies [1].

Alkbh8-knockout (Albkh8 -/-) mice studies have revealed its significance. These mice showed reduced 5-methoxycarbonylmethyluridine levels, abnormal behaviors indicating central nervous system dysfunction, and ischemic pathological changes in the cerebral cortex and hippocampus [1]. Neurons and glial cells from these mice also had reduced mitochondrial membrane potential [1]. In Drosophila, ALKBH8 null animals lacked wobble uridine methylation, had reduced protein synthesis in the nervous system, and exhibited ectopic synapse formation and memory impairments, which were reversed by antioxidant treatment [3].

In conclusion, Alkbh8 is crucial for maintaining neural function through oxidative stress-regulatory mechanisms and for proper synapse formation and memory in the nervous system. Its loss-of-function models have provided insights into its role in central nervous system-related diseases and intellectual disability disorders [1,3].

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. 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/