Nuclear TDP-43 causes neuronal toxicity by escaping from the inhibitory regulation by hnRNPs.
Dysregulation of transactive response DNA-binding protein-43 (TDP-43) is thought to be linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 normally localizes in the nucleus but its main localization shifts to the cytoplasm in most affected cells of ALS and FTLD patients. It is not yet known whether nuclear or cytoplasmic TDP-43 is responsible for TDP-43-induced neurotoxicity. In this study, we show that nuclear TDP-43 causes TDP-43 neurotoxicity. DNA/RNA-binding and dimerization of TDP-43 are both essential for TDP-43-induced cell death. Moreover, endogenous heterogeneous nuclear ribonucleoprotein-U (hnRNP-U) binds to TDP-43 and knocking-down of hnRNP-U induces neurotoxicity, whereas overexpression of hnRNP-U or hnRNP-A2 inhibits TDP-43-induced neurotoxicity. In addition, hnRNP-U inhibits TDP-43-mediated alterations in splicing of POLDIP3 mRNA. Altogether, these results suggest that nuclear TDP-43 becomes neurotoxic by escaping from the inhibitory regulation by hnRNPs.
Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
Hiroaki
H
Suzuki
Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Yoshio
Y
Shibagaki
Division of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Seisuke
S
Hattori
Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan sakimatu@tokyo-med.ac.jp.
Masaaki
M
Matsuoka
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000633:toxicity; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D034722:Heterogeneous-Nuclear Ribonucleoprotein U / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D021381:Protein Transport; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000235:genetics
D004268:DNA-Binding Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034722:Heterogeneous-Nuclear Ribonucleoprotein U; D009687:Nuclear Proteins; C495327:POLDIP3 protein, human; D016601:RNA-Binding Proteins; C000598624:TARDBP protein, human; C439768:hnRNP A2