title: The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity.
abstract: Genetic mutations in TAR DNA-binding protein 43 (TARDBP, also known as TDP-43) cause amyotrophic lateral sclerosis (ALS), and an increase in the presence of TDP-43 (encoded by TARDBP) in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Wenzhang
authors.identifier: 0000-0003-4426-019X
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Luwen
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pediatric Newborn Medicine, Brigham &Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Siedlak
authors.affiliation: Electron Microscopy Core Facility, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujioka
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Sirui
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Xiaopin
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of Molecular Pharmacology &Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Edroaldo Lummertz
authors.identifier: 0000-0003-0537-4223
authors.initials: EL
authors.lastname: da Rocha
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Sheng
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Heewon
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Lerou
authors.affiliation: Department of Molecular Pharmacology &Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Xinglong
authors.initials: X
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger
chemical_list: D004268:DNA-Binding Proteins; D042967:Electron Transport Complex I; D009245:NADH Dehydrogenase; D012333:RNA, Messenger; C000598624:TARDBP protein, human; C578077:Tardbp protein, mouse; C507225:MT-ND6 protein, human; C114961:MT-ND3 protein, human