title: Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts.
abstract: An expanded hexanucleotide repeat in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia (c9FTD/ALS). Therapeutics are being developed to target RNAs containing the expanded repeat sequence (GGGGCC); however, this approach is complicated by the presence of antisense strand transcription of expanded GGCCCC repeats. We found that targeting the transcription elongation factor Spt4 selectively decreased production of both sense and antisense expanded transcripts, as well as their translated dipeptide repeat (DPR) products, and also mitigated degeneration in animal models. Knockdown of SUPT4H1, the human Spt4 ortholog, similarly decreased production of sense and antisense RNA foci, as well as DPR proteins, in patient cells. Therapeutic targeting of a single factor to eliminate c9FTD/ALS pathological features offers advantages over approaches that require targeting sense and antisense repeats separately.
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
authors: Nicholas J
authors: NJ
authors: Kramer
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Yari
authors: Y
authors: Carlomagno
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Yong-Jie
authors: YJ
authors: Zhang
authors: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Sandra
authors: S
authors: Almeida
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Casey N
authors: CN
authors: Cook
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Tania F
authors: TF
authors: Gendron
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Mercedes
authors: M
authors: Prudencio
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Marka
authors: M
authors: Van Blitterswijk
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Veronique
authors: V
authors: Belzil
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors: Julien
authors: J
authors: Couthouis
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors: Joseph West
authors: JW
authors: Paul
authors: Department of Biology and Neuroscience Graduate Program, University of Pennsylvania, Philadelphia, PA, USA.
authors: Lindsey D
authors: LD
authors: Goodman
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Lillian
authors: L
authors: Daughrity
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Jeannie
authors: J
authors: Chew
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Aliesha
authors: A
authors: Garrett
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Luc
authors: L
authors: Pregent
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Karen
authors: K
authors: Jansen-West
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Lilia J
authors: LJ
authors: Tabassian
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Rosa
authors: R
authors: Rademakers
authors: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors: Kevin
authors: K
authors: Boylan
authors: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors: Neill R
authors: NR
authors: Graff-Radford
authors: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors: Keith A
authors: KA
authors: Josephs
authors: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors: Joseph E
authors: JE
authors: Parisi
authors: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors: David S
authors: DS
authors: Knopman
authors: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors: Ronald C
authors: RC
authors: Petersen
authors: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors: Bradley F
authors: BF
authors: Boeve
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors: Ning
authors: N
authors: Deng
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors: Yanan
authors: Y
authors: Feng
authors: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors: Tzu-Hao
authors: TH
authors: Cheng
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors: Dennis W
authors: DW
authors: Dickson
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
authors: Stanley N
authors: SN
authors: Cohen
authors: Department of Biology and Neuroscience Graduate Program, University of Pennsylvania, Philadelphia, PA, USA.
authors: Nancy M
authors: NM
authors: Bonini
authors: Department of Integrative Physiology, University of Colorado, Boulder, CO, USA.
authors: Christopher D
authors: CD
authors: Link
authors: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors: Fen-Biao
authors: FB
authors: Gao
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. agitler@stanford.edu petrucelli.leonard@mayo.edu.
authors: Leonard
authors: L
authors: Petrucelli
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. agitler@stanford.edu petrucelli.leonard@mayo.edu.
authors: Aaron D
authors: AD
authors: Gitler
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D000073885:C9orf72 Protein; D017173:Caenorhabditis elegans; D002478:Cells, Cultured; D042622:DNA Repeat Expansion; D004151:Dipeptides / Q000235:genetics; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D057180:Frontotemporal Dementia / Q000235:genetics*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004151:Dipeptides; D009687:Nuclear Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C080991:SPT4 protein, S cerevisiae; C481011:SUPT4H1 protein, human; D029701:Saccharomyces cerevisiae Proteins; D035602:Transcriptional Elongation Factors