Ly6h, a member of the lymphocyte antigen-6 (LY6) gene family, is located on human chromosomes 6, 8, 11, and 19 [1,4]. The LY6 gene family proteins are characterized by the presence of LU domains [1,4]. Ly6h is involved in regulating the trafficking of α7 nicotinic acetylcholine receptors (α7 nAChRs) [2,3,5]. α7 nAChRs are important for synaptic signaling, gene transcription, and plastic changes in the brain, and Ly6h may be relevant to plastic changes in the nervous system, including those during nicotine addiction and in Alzheimer's disease [2,3].

Knockdown of Ly6h in rat hippocampal pyramidal neurons enhances nicotine-induced potentiation of glutamatergic mEPSC amplitude, suggesting its role in regulating glutamatergic circuitry during nicotine addiction [2]. In Alzheimer's disease, amyloid β -driven reduction in Ly6h perturbs the balance between Ly6h and NACHO, leading to increased phosphorylated tau and α7 -mediated neurotoxicity. Ly6h release into human CSF is also correlated with AD severity [3].

In summary, Ly6h plays a crucial role in regulating α7 nAChRs, which is relevant to synaptic and plastic changes in the nervous system. Findings from knockdown experiments in neurons have revealed its significance in nicotine-related neural plasticity and in the pathogenesis of Alzheimer's disease, highlighting its potential as a biomarker and therapeutic target in these disease areas.

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. Upadhyay, Geeta. 2019. Emerging Role of Lymphocyte Antigen-6 Family of Genes in Cancer and Immune Cells. In Frontiers in immunology, 10, 819. doi:10.3389/fimmu.2019.00819. https://pubmed.ncbi.nlm.nih.gov/31068932/

5. 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/