Alexander disease:the road ahead  

作　　者：María A.Pajares Elena Hernández-Gerez Milos Pekny Dolores Pérez-Sala 

机构地区：[1]Department of Structural and Chemical Biology,Centro de Investigaciones Biológicas Margarita Salas,Madrid,Spain [2]Laboratory of Astrocyte Biology and CNS Regeneration,Center for Brain Repair,Department of Clinical Neuroscience,Institute of Neuroscience and Physiology,Sahlgrenska Academy at the University of Gothenburg,Gothenburg,Sweden [3]University of Newcastle,Newcastle,NSW,and the Florey Institute of Neuroscience and Mental Health,Parkville,VIC,Australia

出　　处：《Neural Regeneration Research》2023年第10期2156-2160,共5页中国神经再生研究（英文版）

基　　金：Work at the authors’laboratories is supported by grants from"la Caixa"Foundation;Grant Agreement LCF/PR/HR21/52410002;EJP RD COFUND-EJP N°825575"Alexander"to DPS and MP;Agencia Estatal de Investigacion,MICINN and ERDF Grant No.RTI2018-097624-B-I00 and PID2021-126827OB-I00 to DPS;grants from the Swedish Research Council(2017-02255);ALF Gothenburg(146051);The Swedish Society for Medical Research,Hj?rnfonden,S?derberg’s Foundations,Hagstr?mer’s Foundation Millennium,Ami?v’s Foundation,E.Jacobson’s Donation Fund,the Swedish Stroke Foundation,NanoNet COST Action(BM1002),EU FP 7 Program TargetBraln(279017)to MP。

摘　　要：Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and adult onsets of the disease are known and,in both cases,astrocytes present characteristic aggregates,named Rosenthal fibers.Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner.Although the presence of aggregates suggests a proteostasis problem of the mutant forms,this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased.Additionally,several isoforms of glial fibrillary acidic protein have been described to date,while the impact of the mutations on their expression and proportion has not been exhaustively studied.Moreover,the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered,leading to functional changes that may modify the morphology,positioning,and/or the function of several organelles,in turn,impairing astrocyte normal function and subsequently affecting neurons.In particular,mitochondrial function,redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes.To study the disease and to develop putative therapeutic strategies,several experimental models have been developed,a collection that is in constant growth.The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations,together with the availability of new and more relevant experimental models,holds promise for the design and assay of novel therapeutic strategies.

关 键 词：ASTROCYTES endoplasmic reticulum stress glial fibrillary acidic protein mutants metabolism misassembly MISFOLDING NEURODEGENERATION oxidative stress posttranslational modifications unfolded protein response 

分 类 号：R741[医药卫生—神经病学与精神病学]