Format

Send to

Choose Destination
Science. 2016 Aug 12;353(6300):708-12. doi: 10.1126/science.aaf7791.

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

Author information

1
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
2
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
3
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
4
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
5
Department of Biology and Neuroscience Graduate Program, University of Pennsylvania, Philadelphia, PA, USA.
6
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
7
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
8
Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China.
9
Department of Integrative Physiology, University of Colorado, Boulder, CO, USA.
10
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. agitler@stanford.edu petrucelli.leonard@mayo.edu.
11
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. agitler@stanford.edu petrucelli.leonard@mayo.edu.

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.

PMID:
27516603
PMCID:
PMC5823025
DOI:
10.1126/science.aaf7791
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center