Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 242, Taiwan.
Int J Mol Sci. 2021 Mar 23;22(6):3278. doi: 10.3390/ijms22063278.
Glycine N-methyltransferase (GNMT) regulates S-adenosylmethionine (SAMe), a methyl donor in methylation. Over-expressed SAMe may cause neurogenic capacity reduction and memory impairment. GNMT knockout mice (GNMT-KO) was applied as an experimental model to evaluate its effect on neurons. In this study, proteins from brain tissues were studied using proteomic approaches, Haemotoxylin and Eosin staining, immunohistochemistry, Western blotting, and ingenuity pathway analysis. The expression of Receptor-interacting protein 1(RIPK1) and Caspase 3 were up-regulated and activity-dependent neuroprotective protein (ADNP) was down-regulated in GNMT-KO mice regardless of the age. Besides, proteins related to neuropathology, such as excitatory amino acid transporter 2, calcium/calmodulin-dependent protein kinase type II subunit alpha, and Cu-Zn superoxide dismutase were found only in the group of aged wild-type mice; 4-aminobutyrate amino transferase, limbic system-associated membrane protein, sodium- and chloride-dependent GABA transporter 3 and ProSAAS were found only in the group of young GNMT-KO mice and are related to function of neurons; serum albumin and Rho GDP dissociation inhibitor 1 were found only in the group of aged GNMT-KO mice and are connected to neurodegenerative disorders. With proteomic analyses, a pathway involving Gonadotropin-releasing hormone (GnRH) signal was found to be associated with aging. The GnRH pathway could provide additional information on the mechanism of aging and non-aging related neurodegeneration, and these protein markers may be served in developing future therapeutic treatments to ameliorate aging and prevent diseases.
甘氨酸 N-甲基转移酶（GNMT）调节 S-腺苷甲硫氨酸（SAMe），SAMe 是甲基供体在甲基化中的作用。高表达的 SAMe 可能导致神经发生能力降低和记忆障碍。GNMT 基因敲除（GNMT-KO）小鼠被应用于评估其对神经元的影响的实验模型。在这项研究中，使用蛋白质组学方法、苏木精和伊红染色、免疫组织化学、Western blot 和 ingenuity 通路分析研究脑组织中的蛋白质。无论年龄大小，GNMT-KO 小鼠的受体相互作用蛋白 1（RIPK1）和半胱天冬酶 3 的表达上调，活性依赖性神保护蛋白（ADNP）下调。此外，兴奋性氨基酸转运蛋白 2、钙/钙调蛋白依赖性蛋白激酶 II 亚基 α 和铜锌超氧化物歧化酶等与神经病理学相关的蛋白质仅在老年野生型小鼠组中发现；4-氨基丁酸转氨酶、边缘系统相关膜蛋白、钠和氯离子依赖性 GABA 转运体 3 和 ProSAAS 仅在年轻的 GNMT-KO 小鼠组中发现，与神经元功能有关；血清白蛋白和 Rho GDP 解离抑制剂 1 仅在老年 GNMT-KO 小鼠组中发现，与神经退行性疾病有关。通过蛋白质组学分析，发现与促性腺激素释放激素（GnRH）信号相关的途径与衰老有关。GnRH 途径可以为衰老和非衰老相关神经退行性变的机制提供额外的信息，这些蛋白质标志物可能用于开发未来的治疗方法，以改善衰老和预防疾病。
