14-3-3蛋白维持中枢神经系统髓鞘发育不良型细直径轴突的稳态OA
在中枢神经系统中,少突胶质细胞包绕神经轴突形成的髓鞘可保障动作电位高效传导,并维持轴突稳态。因此,在多发性硬化(MS)等脱髓鞘疾病中,可观察到轴突发生变性、丢失,尤以细直径轴突更为显著。Teneurin 4敲除(Ten 4-/-)小鼠存在严重的细直径轴突髓鞘发育不良,但小鼠生存期可超过1年。本研究利用Ten 4-/-小鼠,旨在阐明无髓鞘包裹状态下细直径轴突得以存活的分子机制。免疫组化分析结果显示,神经丝染色呈异常弥散且染色强度增高;同时,Ten 4-/-小鼠体内非磷酸化神经丝与淀粉样前体蛋白的免疫组化信号水平升高。透射电镜分析得到意外发现:即便不存在致密髓鞘,1岁Ten 4-/-小鼠的细直径轴突依然存活。为解析其分子机制,本研究对Ten 4-/-小鼠脑组织开展质谱蛋白质组学分析。结果显示,7种14-3-3亚型中有4种在Ten 4-/-小鼠细直径轴突中高表达。最后,使用14-3-3抑制剂BV02与difopein抑制Ten 4-/-小鼠体内14-3-3蛋白功能后,观察到细直径轴突损伤进一步加重。综上,14-3-3蛋白家族是髓鞘发育不良细直径轴突的促存活因子。本研究结果有助于进一步揭示多发性硬化等脱髓鞘疾病的发病机制,并可为新型治疗手段的研发提供参考。
Nanako Yamada;Hinako Saito;Riko Takahashi;Mio Fujisato;Yukina Hosoda;Binri Sasaki;Momona Yamada;Sakurako Abe;Chikako Hayashi;Akira Yoshimoto;Ryunosuke Ohkawa;Tomal Julian Matt;Florence M Bareyre;Stefan Berghoff;Mikael Simons;Nobuharu Suzuki;王晶(编译)
Department of Clinical Bioanalysis and Molecular Biology,Graduate School of Medical and Dental Sciences,Institute of Science Tokyo/Tokyo Medical and Dental University(TMDU),Tokyo,JapanDepartment of Clinical Bioanalysis and Molecular Biology,Graduate School of Medical and Dental Sciences,Institute of Science Tokyo/Tokyo Medical and Dental University(TMDU),Tokyo,Japan Department of Molecular and Cellular Biology,Graduate School of Medical and Dental Sciences,TMDU,Tokyo,Japan Division of Surgical Pathology,Institute of Science Tokyo Hospital,Tokyo,JapanDepartment of Molecular and Cellular Biology,Graduate School of Medical and Dental Sciences,TMDU,Tokyo,JapanDepartment of Clinical Bioanalysis and Molecular Biology,Graduate School of Medical and Dental Sciences,Institute of Science Tokyo/Tokyo Medical and Dental University(TMDU),Tokyo,JapanDepartment of Molecular and Cellular Biology,Graduate School of Medical and Dental Sciences,TMDU,Tokyo,JapanDepartment of Clinical Bioanalysis and Molecular Biology,Graduate School of Medical and Dental Sciences,Institute of Science Tokyo/Tokyo Medical and Dental University(TMDU),Tokyo,JapanDepartment of Molecular and Cellular Biology,Graduate School of Medical and Dental Sciences,TMDU,Tokyo,JapanDepartment of Clinical Bioanalysis and Molecular Biology,Graduate School of Medical and Dental Sciences,Institute of Science Tokyo/Tokyo Medical and Dental University(TMDU),Tokyo,JapanDepartment of Molecular and Cellular Biology,Graduate School of Medical and Dental Sciences,TMDU,Tokyo,JapanDepartment of Clinical Bioanalysis and Molecular Biology,Graduate School of Medical and Dental Sciences,Institute of Science Tokyo/Tokyo Medical and Dental University(TMDU),Tokyo,JapanDepartment of Clinical Bioanalysis and Molecular Biology,Graduate School of Medical and Dental Sciences,Institute of Science Tokyo/Tokyo Medical and Dental University(TMDU),Tokyo,JapanInstitute of Clinical Neuroimmunology,University Hospital,LMU Munich,Munich,Germany Biomedical Center Munich,Medical Faculty,LMU Munich,Munich,Germany Munich Cluster of Systems Neurology,Munich,GermanyInstitute of Clinical Neuroimmunology,University Hospital,LMU Munich,Munich,Germany Biomedical Center Munich,Medical Faculty,LMU Munich,Munich,Germany Munich Cluster of Systems Neurology,Munich,GermanyInstitute of Neuronal Cell Biology,Technical University Munich,Munich,Germany German Center for Neurodegenerative Diseases,Munich,GermanyInstitute of Neuronal Cell Biology,Technical University Munich,Munich,Germany German Center for Neurodegenerative Diseases,Munich,GermanyDepartment of Clinical Bioanalysis and Molecular Biology,Graduate School of Medical and Dental Sciences,Institute of Science Tokyo/Tokyo Medical and Dental University(TMDU),Tokyo,Japan Department of Molecular and Cellular Biology,Graduate School of Medical and Dental Sciences,TMDU,Tokyo,Japan
医药卫生
14-3-3轴突髓鞘
《神经损伤与功能重建》 2026 (9)
P.F0003-F0003,1
评论