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Neuron. 2014 Sep 3;83(5):1043-50. doi: 10.1016/j.neuron.2014.07.041. Epub 2014 Aug 14.

Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS.

Author information

1
Department of Chemistry, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1, Jupiter, FL 33458, USA.
2
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.
3
Department of Neurology, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.
4
Department of Neurology, University of Michigan, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.
5
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA 02115, USA.
6
Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
7
Spasticity and Spinal Physiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
8
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
9
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Via Zucchi, 18, 20095 Cusano Milanino (Milan), Italy.
10
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Via Zucchi, 18, 20095 Cusano Milanino (Milan), Italy; Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Via Sforza, 35, 20122, Milan, Italy.
11
Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Via Sforza, 35, 20122, Milan, Italy; Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
12
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
13
Department of Neurology, Brain Science Institute, Johns Hopkins University, 855 N Wolfe Street, Baltimore, MD 21205, USA.
14
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA. Electronic address: petrucelli.leonard@mayo.edu.
15
Department of Chemistry, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1, Jupiter, FL 33458, USA. Electronic address: disney@scripps.edu.

Erratum in

  • Neuron. 2014 Oct 1;84(1):239.

Abstract

A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). RNA of the expanded repeat (r(GGGGCC)exp) forms nuclear foci or undergoes repeat-associated non-ATG (RAN) translation, producing "c9RAN proteins." Since neutralizing r(GGGGCC)exp could inhibit these potentially toxic events, we sought to identify small-molecule binders of r(GGGGCC)exp. Chemical and enzymatic probing of r(GGGGCC)8 indicate that it adopts a hairpin structure in equilibrium with a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC)66 and neurons transdifferentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RAN proteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)exp-binding small molecules as a possible c9FTD/ALS therapeutic and suggest that c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.

PMID:
25132468
PMCID:
PMC4232217
DOI:
10.1016/j.neuron.2014.07.041
[Indexed for MEDLINE]
Free PMC Article

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