title: Neurodegeneration-associated TDP-43 interacts with fragile X mental retardation protein (FMRP)/Staufen (STAU1) and regulates SIRT1 expression in neuronal cells.
abstract: Despite the identification of the 43 kDa transactive response DNA-binding protein (TDP-43) as a major pathological signatory protein in a wide range of neurodegenerative diseases, the mechanistic role of TDP-43 in neurodegenerative disorders is still poorly understood. Here, we report that TDP-43 is physically associated with fragile X mental retardation protein (FMRP) and Staufen (STAU1) to form a functional complex. Differential microarray analysis revealed that the expression of a collection of functionally important genes including Sirtuin (SIRT1) is regulated by this complex. RNA-immunoprecipitation (RIP) and RNA pull-down assays demonstrated that TDP-43/FMRP/STAU1 specifically binds to the 3'-UTR of SIRT1 mRNA, and that knockdown the expression of any one of these three proteins resulted in the reduction of SIRT1 mRNA and protein. SIRT1 is implicated in double-stranded DNA break repair and is required for cell survival. Indeed, depletion of TDP-43/FMRP/STAU1 sensitizes cells to apoptosis and DNA damages. Collectively, our results revealed a molecular mechanism for the cellular function of TDP-43 and might shed new light on the understanding of the mechanistic role of TDP-43 in neurodegenerative diseases.
authors.affiliation: The Third Hospital, Peking University, Beijing 100191, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Yu
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Fan
authors.forename: Bin
authors.initials: B
authors.lastname: Gui
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Chenghao
authors.initials: C
authors.lastname: Xuan
authors.forename: Lin
authors.initials: L
authors.lastname: Shan
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Shang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions / Q000502:physiology; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009447:Neuroblastoma; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D056564:Sirtuin 1; C497683:FMR1 protein, human; C492185:STAU1 protein, human; C447939:SIRT1 protein, human