Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS

Zhaoming Su; Yongjie Zhang; Tania F. Gendron; Peter O. Bauer; Jeannie Chew; Wang Yong Yang; Erik Fostvedt; Karen Jansen-West; Veronique V. Belzil; Pamela Desaro; Amelia Johnston; Karen Overstreet; Seok Yoon Oh; Peter K. Todd; James D. Berry; Merit E. Cudkowicz; Bradley F. Boeve; Dennis Dickson; Mary Kay Floeter; Bryan J. Traynor; Claudia Morelli; Antonia Ratti; Vincenzo Silani; Rosa Rademakers; Robert H. Brown; Jeffrey D. Rothstein; Kevin B. Boylan; Leonard Petrucelli; Matthew D. Disney

doi:10.1016/j.neuron.2014.07.041

Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS

Zhaoming Su, Yongjie Zhang, Tania F. Gendron, Peter O. Bauer, Jeannie Chew, Wang Yong Yang, Erik Fostvedt, Karen Jansen-West, Veronique V. Belzil, Pamela Desaro, Amelia Johnston, Karen Overstreet, Seok Yoon Oh, Peter K. Todd, James D. Berry, Merit E. Cudkowicz, Bradley F. Boeve, Dennis Dickson, Mary Kay Floeter, Bryan J. TraynorClaudia Morelli, Antonia Ratti, Vincenzo Silani, Rosa Rademakers, Robert H. Brown, Jeffrey D. Rothstein, Kevin B. Boylan, Leonard Petrucelli, Matthew D. Disney

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205 Scopus citations

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 aquadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)_exp were designed and found to significantly inhibit RANtranslation 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/ALStherapeutic and suggest that c9RAN proteins couldpotentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)_exp.

Original language	English (US)
Pages (from-to)	1043-1050
Number of pages	8
Journal	Neuron
Volume	83
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2014.07.041
State	Published - Sep 3 2014

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2014.07.041

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Su, Z., Zhang, Y., Gendron, T. F., Bauer, P. O., Chew, J., Yang, W. Y., Fostvedt, E., Jansen-West, K., Belzil, V. V., Desaro, P., Johnston, A., Overstreet, K., Oh, S. Y., Todd, P. K., Berry, J. D., Cudkowicz, M. E., Boeve, B. F., Dickson, D., Floeter, M. K., ... Disney, M. D. (2014). Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS. Neuron, 83(5), 1043-1050. https://doi.org/10.1016/j.neuron.2014.07.041

Su, Z, Zhang, Y , Gendron, TF, Bauer, PO, Chew, J, Yang, WY, Fostvedt, E, Jansen-West, K, Belzil, VV, Desaro, P, Johnston, A, Overstreet, K, Oh, SY, Todd, PK, Berry, JD, Cudkowicz, ME, Boeve, BF , Dickson, D, Floeter, MK, Traynor, BJ, Morelli, C, Ratti, A, Silani, V, Rademakers, R, Brown, RH, Rothstein, JD, Boylan, KB, Petrucelli, L & Disney, MD 2014, 'Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS', Neuron, vol. 83, no. 5, pp. 1043-1050. https://doi.org/10.1016/j.neuron.2014.07.041

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title = "Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS",

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 aquadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RANtranslation 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/ALStherapeutic and suggest that c9RAN proteins couldpotentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.",

author = "Zhaoming Su and Yongjie Zhang and Gendron, {Tania F.} and Bauer, {Peter O.} and Jeannie Chew and Yang, {Wang Yong} and Erik Fostvedt and Karen Jansen-West and Belzil, {Veronique V.} and Pamela Desaro and Amelia Johnston and Karen Overstreet and Oh, {Seok Yoon} and Todd, {Peter K.} and Berry, {James D.} and Cudkowicz, {Merit E.} and Boeve, {Bradley F.} and Dennis Dickson and Floeter, {Mary Kay} and Traynor, {Bryan J.} and Claudia Morelli and Antonia Ratti and Vincenzo Silani and Rosa Rademakers and Brown, {Robert H.} and Rothstein, {Jeffrey D.} and Boylan, {Kevin B.} and Leonard Petrucelli and Disney, {Matthew D.}",

note = "Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",

year = "2014",

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doi = "10.1016/j.neuron.2014.07.041",

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T1 - Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS

AU - Su, Zhaoming

AU - Zhang, Yongjie

AU - Gendron, Tania F.

AU - Bauer, Peter O.

AU - Chew, Jeannie

AU - Yang, Wang Yong

AU - Fostvedt, Erik

AU - Jansen-West, Karen

AU - Belzil, Veronique V.

AU - Desaro, Pamela

AU - Johnston, Amelia

AU - Overstreet, Karen

AU - Oh, Seok Yoon

AU - Todd, Peter K.

AU - Berry, James D.

AU - Cudkowicz, Merit E.

AU - Boeve, Bradley F.

AU - Dickson, Dennis

AU - Floeter, Mary Kay

AU - Traynor, Bryan J.

AU - Morelli, Claudia

AU - Ratti, Antonia

AU - Silani, Vincenzo

AU - Rademakers, Rosa

AU - Brown, Robert H.

AU - Rothstein, Jeffrey D.

AU - Boylan, Kevin B.

AU - Petrucelli, Leonard

AU - Disney, Matthew D.

PY - 2014/9/3

Y1 - 2014/9/3

N2 - 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 aquadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RANtranslation 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/ALStherapeutic and suggest that c9RAN proteins couldpotentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.

AB - 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 aquadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RANtranslation 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/ALStherapeutic and suggest that c9RAN proteins couldpotentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.

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JO - Neuron

JF - Neuron

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Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS

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