Superresolution live-cell imaging reveals that the localization of TMEM106B to filopodia in oligodendrocytes is compromised by the hypomyelination-related D252N mutation

查看全文 作　　者：Shijia [1]Xing;Xiaolu [1]Zheng;Huifang [2]Yan;Yanquan [1]Mo;Ruoyu [2,6]Duan;Zhixing [4]Chen;Kunhao [5]Wang;Kai [2]Gao;Tongsheng [5]Chen;Shiqun [1]Zhao;Jingmin [2]Wang;Liangyi [1,3]Chen 机构地区：[1]National Biomedical Imaging Center,State Key Laboratory of Membrane Biology,Beijing Key Laboratory of Cardiometabolic Molecular Medicine,Institute of Molecular Medicine,College of Future Technology,Peking University,Beijing 100871,China;[2]Department of Pediatrics,Peking University First Hospital,Beijing 100034,China;[3]PKU-IDG/McGovern Institute for Brain Research,Beijing 100871,China;[4]National Biomedical Imaging Center,Institute of Molecular Medicine,College of Future Technology,Peking University,Beijing 100871,China;[5]Key Laboratory of Laser Life Science,Ministry of Education,College of Biophotonics,South China Normal University,Guangzhou 510631,China;[6]National Center for Children’s Health,Department of Neurology,Beijing Children’s Hospital,Capital Medical University,Beijing 100045,China 出　　处：《Science China(Life Sciences)》索引2023年第66卷第8期,共11页 基　　金：supported by the National Natural Science Foundation of China(81925022,61827825,32227802,92054301);the Fundamental Research Center Project of the National Natural Science Foundation of China(T2288102);the National Science and Technology Major Project Program(2022YFC3400600);Beijing Natural Science Foundation Key Research Topics(Z20J00059);UMHS-PUHSC Joint Institute for Translational and Clinical Research(BMU2019JI009);Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases(BZ0317);China Postdoctoral Science Foundation(2021M690465)。 摘　　要：Hypomyelination leukodystrophies constitute a group of heritable white matter disorders exhibiting defective myelin development.Initially identified as a lysosomal protein,the TMEM106B D252N mutant has recently been associated with hypomyelination.However,how lysosomal TMEM106B facilitates myelination and how the D252N mutation disrupts that process are poorly understood.We used superresolution Hessian structured illumination microscopy(Hessian-SIM)and spinning discconfocal structured illumination microscopy(SD-SIM)to find that the wild-type TMEM106B protein is targeted to the plasma membrane,filopodia,and lysosomes in human oligodendrocytes.The D252N mutation reduces the size of lysosomes in oligodendrocytes and compromises lysosome changes upon starvation stress.Most importantly,we detected reductions in the length and number of filopodia in cells expressing the D252N mutant.PLP1 is the most abundant myelin protein that almost entirely colocalizes with TMEM106B,and coexpressing PLP1 with the D252N mutant readily rescues the lysosome and filopodia phenotypes of cells.Therefore,interactions between TMEM106B and PLP1 on the plasma membrane are essential for filopodia formation and myelination in oligodendrocytes,which may be sustained by the delivery of these proteins from lysosomes via exocytosis. 关 键 词：superresolution imaging OLIGODENDROCYTE TMEM106B LYSOSOME FILOPODIA