Details

Autor(en) / Beteiligte

• Ash, Peter E.A.
• Bieniek, Kevin F.
• Gendron, Tania F.
• Caulfield, Thomas
• Lin, Wen-Lang
• DeJesus-Hernandez, Mariely
• van Blitterswijk, Marka M.
• Jansen-West, Karen
• Paul, Joseph W.
• Rademakers, Rosa
• Boylan, Kevin B.
• Dickson, Dennis W.
• Petrucelli, Leonard

Titel

Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS

Ist Teil von

• Neuron (Cambridge, Mass.), 2013-02, Vol.77 (4), p.639-646

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders with clinical, genetic, and neuropathological overlap. Hexanucleotide (GGGGCC) repeat expansions in a noncoding region of C9ORF72 are the major genetic cause of FTD and ALS (c9FTD/ALS). The RNA structure of GGGGCC repeats renders these transcripts susceptible to an unconventional mechanism of translation—repeat-associated non-ATG (RAN) translation. Antibodies generated against putative GGGGCC repeat RAN-translated peptides (anti-C9RANT) detected high molecular weight, insoluble material in brain homogenates, and neuronal inclusions throughout the CNS of c9FTD/ALS cases. C9RANT immunoreactivity was not found in other neurodegenerative diseases, including CAG repeat disorders, or in peripheral tissues of c9FTD/ALS. The specificity of C9RANT for c9FTD/ALS is a potential biomarker for this most common cause of FTD and ALS. These findings have significant implications for treatment strategies directed at RAN-translated peptides and their aggregation and the RNA structures necessary for their production. ► C9ORF72-expanded GGGGCC repeat RNA undergoes unconventional translation ► A C9ORF72 RAN translation product accumulates in insoluble inclusions in the brain ► Inclusions are specific to c9FTD/ALS and not in other neurodegenerative disorders ► C9ORF72 RAN translation peptides maybe a potential biomarker and therapeutic target The study by Ash et al. details unconventional repeat-associated non-ATG translation in frontotemporal dementia and amyotrophic lateral sclerosis with C9ORF72 GGGGCC repeat expansion (c9FTD/ALS). This pathologic product is highly specific to c9FTD/ALS, serving as a potential biomarker and therapeutic target.