Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts

Nicholas J. Kramer, Yari Carlomagno, Yongjie Zhang, Sandra Almeida, Casey Cook, Tania D Gendron, Mercedes Prudencio, Marka Van Blitterswijk, Veronique Belzil, Julien Couthouis, Joseph West Paul, Lindsey D. Goodman, Lillian Daughrity, Jeannie Chew, Aliesha Garrett, Luc Pregent, Karen Jansen-West, Lilia J. Tabassian, Rosa V Rademakers, Kevin BoylanNeill R Graff Radford, Keith Anthony Josephs, Joseph E Parisi, David S Knopman, Ronald Carl Petersen, Bradley F Boeve, Ning Deng, Yanan Feng, Tzu Hao Cheng, Dennis W Dickson, Stanley N. Cohen, Nancy M. Bonini, Christopher D. Link, Fen Biao Gao, Leonard Petrucelli, Aaron D. Gitler

Research output: Contribution to journalArticle

49 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)708-712
Number of pages5
JournalScience
Volume353
Issue number6300
DOIs
StatePublished - Aug 12 2016

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Dipeptides
Peptide Elongation Factors
Antisense RNA
Transcription Factors
Animal Models
RNA
Therapeutics
Proteins
Frontotemporal Dementia With Motor Neuron Disease

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts. / Kramer, Nicholas J.; Carlomagno, Yari; Zhang, Yongjie; Almeida, Sandra; Cook, Casey; Gendron, Tania D; Prudencio, Mercedes; Van Blitterswijk, Marka; Belzil, Veronique; Couthouis, Julien; Paul, Joseph West; Goodman, Lindsey D.; Daughrity, Lillian; Chew, Jeannie; Garrett, Aliesha; Pregent, Luc; Jansen-West, Karen; Tabassian, Lilia J.; Rademakers, Rosa V; Boylan, Kevin; Graff Radford, Neill R; Josephs, Keith Anthony; Parisi, Joseph E; Knopman, David S; Petersen, Ronald Carl; Boeve, Bradley F; Deng, Ning; Feng, Yanan; Cheng, Tzu Hao; Dickson, Dennis W; Cohen, Stanley N.; Bonini, Nancy M.; Link, Christopher D.; Gao, Fen Biao; Petrucelli, Leonard; Gitler, Aaron D.

In: Science, Vol. 353, No. 6300, 12.08.2016, p. 708-712.

Research output: Contribution to journalArticle

Kramer, NJ, Carlomagno, Y, Zhang, Y, Almeida, S, Cook, C, Gendron, TD, Prudencio, M, Van Blitterswijk, M, Belzil, V, Couthouis, J, Paul, JW, Goodman, LD, Daughrity, L, Chew, J, Garrett, A, Pregent, L, Jansen-West, K, Tabassian, LJ, Rademakers, RV, Boylan, K, Graff Radford, NR, Josephs, KA, Parisi, JE, Knopman, DS, Petersen, RC, Boeve, BF, Deng, N, Feng, Y, Cheng, TH, Dickson, DW, Cohen, SN, Bonini, NM, Link, CD, Gao, FB, Petrucelli, L & Gitler, AD 2016, 'Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts', Science, vol. 353, no. 6300, pp. 708-712. https://doi.org/10.1126/science.aaf7791
Kramer, Nicholas J. ; Carlomagno, Yari ; Zhang, Yongjie ; Almeida, Sandra ; Cook, Casey ; Gendron, Tania D ; Prudencio, Mercedes ; Van Blitterswijk, Marka ; Belzil, Veronique ; Couthouis, Julien ; Paul, Joseph West ; Goodman, Lindsey D. ; Daughrity, Lillian ; Chew, Jeannie ; Garrett, Aliesha ; Pregent, Luc ; Jansen-West, Karen ; Tabassian, Lilia J. ; Rademakers, Rosa V ; Boylan, Kevin ; Graff Radford, Neill R ; Josephs, Keith Anthony ; Parisi, Joseph E ; Knopman, David S ; Petersen, Ronald Carl ; Boeve, Bradley F ; Deng, Ning ; Feng, Yanan ; Cheng, Tzu Hao ; Dickson, Dennis W ; Cohen, Stanley N. ; Bonini, Nancy M. ; Link, Christopher D. ; Gao, Fen Biao ; Petrucelli, Leonard ; Gitler, Aaron D. / Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts. In: Science. 2016 ; Vol. 353, No. 6300. pp. 708-712.
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AU - Carlomagno, Yari

AU - Zhang, Yongjie

AU - Almeida, Sandra

AU - Cook, Casey

AU - Gendron, Tania D

AU - Prudencio, Mercedes

AU - Van Blitterswijk, Marka

AU - Belzil, Veronique

AU - Couthouis, Julien

AU - Paul, Joseph West

AU - Goodman, Lindsey D.

AU - Daughrity, Lillian

AU - Chew, Jeannie

AU - Garrett, Aliesha

AU - Pregent, Luc

AU - Jansen-West, Karen

AU - Tabassian, Lilia J.

AU - Rademakers, Rosa V

AU - Boylan, Kevin

AU - Graff Radford, Neill R

AU - Josephs, Keith Anthony

AU - Parisi, Joseph E

AU - Knopman, David S

AU - Petersen, Ronald Carl

AU - Boeve, Bradley F

AU - Deng, Ning

AU - Feng, Yanan

AU - Cheng, Tzu Hao

AU - Dickson, Dennis W

AU - Cohen, Stanley N.

AU - Bonini, Nancy M.

AU - Link, Christopher D.

AU - Gao, Fen Biao

AU - Petrucelli, Leonard

AU - Gitler, Aaron D.

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N2 - 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.

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