title: Poly(GR) in C9ORF72-Related ALS/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC-Derived Motor Neurons.
abstract: GGGGCC repeat expansions in C9ORF72 are the most common genetic cause of both ALS and FTD. To uncover underlying pathogenic mechanisms, we found that DNA damage was greater, in an age-dependent manner, in motor neurons differentiated from iPSCs of multiple C9ORF72 patients than control neurons. Ectopic expression of the dipeptide repeat (DPR) protein (GR)80in iPSC-derived control neurons increased DNA damage, suggesting poly(GR) contributes to DNA damage in aged C9ORF72 neurons. Oxidative stress was also increased in C9ORF72 neurons in an age-dependent manner. Pharmacological or genetic reduction of oxidative stress partially rescued DNA damage in C9ORF72 neurons and control neurons expressing (GR)80or (GR)80-induced cellular toxicity in flies. Moreover, interactome analysis revealed that (GR)80preferentially bound to mitochondrial ribosomal proteins and caused mitochondrial dysfunction. Thus, poly(GR) in C9ORF72 neurons compromises mitochondrial function and causes DNA damage in part by increasing oxidative stress, revealing another pathogenic mechanism in C9ORF72-related ALS and FTD.
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Lopez-Gonzalez
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Yubing
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Karydas
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Helene
authors.initials: H
authors.lastname: Tran
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Dejun
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Almeida
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: fen-biao.gao@umassmed.edu.
authors.forename: Fen-Biao
authors.initials: FB
authors.lastname: Gao
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D015153:Blotting, Western; D000073885:C9orf72 Protein; D002460:Cell Line; D004249:DNA Damage; D042622:DNA Repeat Expansion; D004151:Dipeptides / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism*; D005998:Glycine / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008928:Mitochondria / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides; D011506:Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001120:Arginine; D005998:Glycine
keywords: ALS; C9ORF72; DNA damage; DPR; FTD; RAN translation; iPSC; mitochondria; oxidative stress; repeats