Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Neuron (Cambridge, Mass.), 2014-09, Vol.83 (5), p.1043-1050

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. •(GGGGCC) RNA forms a hairpin structure in equilibrium with a G-quadruplex structure•Neurons directly converted from C9ORF72+ fibroblasts express c9RAN proteins and foci•Small-molecule binders of (GGGGCC)exp RNA ameliorate c9FTD/ALS-associated defects•c9RAN proteins are detected in c9ALS patient cerebrospinal fluid A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis, presumably via the expression of repeat-containing RNA (r(GGGGCC)exp). Su et al. find that small molecules targeting r(GGGGCC)exp can block c9FTD/ALS-associated defects and reveal a potential biomarker for c9FTD/ALS.