Ly6h, a member of the lymphocyte antigen-6 (LY6) gene family, is located on human chromosomes 6, 8, 11 and 19. The LY6 gene family proteins are characterized by the presence of LU domains. Ly6h has been implicated in regulating the trafficking of α7 nicotinic acetylcholine receptors (α7 nAChRs), which are important for synaptic signaling, gene transcription, and plastic changes in the brain [2,3,4]. It also may play a role in both the central nervous system and the immune system [6].

In rat hippocampal pyramidal neurons, knockdown of Ly6h enhances nicotine-induced potentiation of glutamatergic mEPSC amplitude, suggesting its role in regulating plastic changes in the nervous system relevant to nicotine addiction [2]. In Alzheimer's disease, amyloid β -driven reduction in Ly6h perturbs the balance with NACHO, leading to increased phosphorylated tau and α7 -mediated neurotoxicity, and Ly6h release into human CSF is correlated with AD severity [3]. In glioma -related epilepsy, the expression levels of LY6H were markedly reduced, and it shows potential as a biomarker for early detection [5]. Pan -cancer analysis reveals that LY6H is highly expressed in most cancers, has early diagnostic potential in 12 tumors, and shows positive or negative correlations with prognosis across different tumor types, and plays a role in regulating immune -infiltrating cells [1].

In conclusion, Ly6h is crucial for regulating α7 nAChRs and has significant implications in multiple disease areas. Its role in nicotine addiction, Alzheimer's disease, glioma -related epilepsy, and various cancers, as revealed through functional studies such as knockdown experiments, provides valuable insights into the underlying biological mechanisms and potential biomarker and therapeutic targets.

References:

1. Qin, Haifei, Lu, Honglong, Qin, Chongjiu, Peng, Tao, Zhu, Guangzhi. 2024. Pan-cancer analysis suggests that LY6H is a potential biomarker of diagnosis, immunoinfiltration, and prognosis. In Journal of Cancer, 15, 5515-5539. doi:10.7150/jca.98449. https://pubmed.ncbi.nlm.nih.gov/39308669/

2. Puddifoot, Clare A, Wu, Meilin, Sung, Rou-Jia, Joiner, William J. . Ly6h regulates trafficking of alpha7 nicotinic acetylcholine receptors and nicotine-induced potentiation of glutamatergic signaling. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 35, 3420-30. doi:10.1523/JNEUROSCI.3630-14.2015. https://pubmed.ncbi.nlm.nih.gov/25716842/

3. Wu, Meilin, Liu, Clifford Z, Barrall, Erika A, Rissman, Robert A, Joiner, William J. 2021. Unbalanced Regulation of α7 nAChRs by Ly6h and NACHO Contributes to Neurotoxicity in Alzheimer's Disease. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 41, 8461-8474. doi:10.1523/JNEUROSCI.0494-21.2021. https://pubmed.ncbi.nlm.nih.gov/34446574/

4. Moriwaki, Yasuhiro, Kubo, Natsuki, Watanabe, Mizuho, Kato, Fusao, Misawa, Hidemi. 2020. Endogenous neurotoxin-like protein Ly6H inhibits alpha7 nicotinic acetylcholine receptor currents at the plasma membrane. In Scientific reports, 10, 11996. doi:10.1038/s41598-020-68947-7. https://pubmed.ncbi.nlm.nih.gov/32686737/

5. Zhang, Zhenpan, Huang, Jianhuang, Lin, Caihou, Liang, Risheng. 2025. Identification and validation of LY6H and GRM3 as candidate biomarkers for Glioma-related epilepsy. In Scientific reports, 15, 12833. doi:10.1038/s41598-025-97333-4. https://pubmed.ncbi.nlm.nih.gov/40229486/

6. Horie, M, Okutomi, K, Taniguchi, Y, Suzuki, M, Takahashi, E. . Isolation and characterization of a new member of the human Ly6 gene family (LY6H). In Genomics, 53, 365-8. doi:. https://pubmed.ncbi.nlm.nih.gov/9799603/