BTBD9, without common aliases noted in the references, is associated with the regulation of the insulin/insulin-like growth factor signaling pathway and has significant importance in neurological function [1]. It is also linked to the ubiquitination and degradation of TNFAIP1, thereby regulating cancer cell migration [6]. Genetic models, especially KO mouse models, have been crucial in understanding its functions.

In knockout models, loss of the BTBD9 homolog in mice (Btbd9) and flies results in RLS-like phenotypes. In Caenorhabditis elegans, loss of hpo-9 (BTBD9 homolog) leads to increased susceptibility to Mn-induced oxidative stress, mitochondrial dysfunction, decreased dopamine levels, and altered dopaminergic neuronal morphology and behavior [1]. In mice, Btbd9 knockout causes enhanced neural activity in the striatum, increased postsynaptic currents in medium spiny neurons, and decreased excitability of cholinergic interneurons. Specific knockout in striatal medium spiny neurons leads to rest-phase motor restlessness, sleep disturbance, and increased thermal sensation [2]. Knockout in the cerebellum affects Purkinje cell activity, causing motor restlessness during the rest phase [3,5]. In the cerebral cortex, knockout results in increased neural activity in certain areas, decreased thickness in parts of the sensorimotor cortex, and enhanced short-term plasticity at corticostriatal terminals, also leading to rest-phase motor restlessness [4].

In conclusion, BTBD9 plays essential roles in regulating oxidative stress, neurotoxicity, and the activity of neurons in multiple brain regions. Btbd9 KO/CKO mouse models have significantly contributed to understanding its role in Restless Legs Syndrome, highlighting its potential as a therapeutic target for this neurological disorder [1-7].

References:

1. Chen, Pan, Cheng, Hong, Zheng, Fuli, Bowman, Aaron B, Aschner, Michael. . BTBD9 attenuates manganese-induced oxidative stress and neurotoxicity by regulating insulin growth factor signaling pathway. In Human molecular genetics, 31, 2207-2222. doi:10.1093/hmg/ddac025. https://pubmed.ncbi.nlm.nih.gov/35134179/

2. Lyu, Shangru, Xing, Hong, DeAndrade, Mark P, Walters, Arthur S, Li, Yuqing. 2019. The Role of BTBD9 in Striatum and Restless Legs Syndrome. In eNeuro, 6, . doi:10.1523/ENEURO.0277-19.2019. https://pubmed.ncbi.nlm.nih.gov/31444227/

3. Lyu, Shangru, Xing, Hong, DeAndrade, Mark P, Walters, Arthur S, Li, Yuqing. 2020. The Role of BTBD9 in the Cerebellum, Sleep-like Behaviors and the Restless Legs Syndrome. In Neuroscience, 440, 85-96. doi:10.1016/j.neuroscience.2020.05.021. https://pubmed.ncbi.nlm.nih.gov/32446853/

4. Lyu, Shangru, Xing, Hong, DeAndrade, Mark P, Febo, Marcelo, Li, Yuqing. 2019. The role of BTBD9 in the cerebral cortex and the pathogenesis of restless legs syndrome. In Experimental neurology, 323, 113111. doi:10.1016/j.expneurol.2019.113111. https://pubmed.ncbi.nlm.nih.gov/31715135/

5. Lyu, Shangru, Xing, Hong, Liu, Yuning, Yokoi, Fumiaki, Li, Yuqing. 2022. Further Studies on the Role of BTBD9 in the Cerebellum, Sleep-like Behaviors and the Restless Legs Syndrome. In Neuroscience, 505, 78-90. doi:10.1016/j.neuroscience.2022.10.008. https://pubmed.ncbi.nlm.nih.gov/36244636/

6. Li, Lihui, Zhang, Wenjuan, Liu, Yue, Wei, Wenyi, Jia, Lijun. 2020. The CRL3BTBD9 E3 ubiquitin ligase complex targets TNFAIP1 for degradation to suppress cancer cell migration. In Signal transduction and targeted therapy, 5, 42. doi:10.1038/s41392-020-0140-z. https://pubmed.ncbi.nlm.nih.gov/32327643/