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

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

Research output: Contribution to journalArticle

524 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)639-646
Number of pages8
JournalNeuron
Volume77
Issue number4
DOIs
StatePublished - Feb 20 2013

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Amyotrophic Lateral Sclerosis
Peptides
Neurodegenerative Diseases
RNA
Biomarkers
Molecular Weight
Antibodies
Brain
Frontotemporal Dementia With Motor Neuron Disease

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS. / Ash, Peter E A; Bieniek, Kevin F.; Gendron, Tania D; Caulfield, Thomas; Lin, Wen Lang; DeJesus-Hernandez, Mariely; Van Blitterswijk, Marka; Jansen-West, Karen; Paul, Joseph W.; Rademakers, Rosa V; Boylan, Kevin B.; Dickson, Dennis W; Petrucelli, Leonard.

In: Neuron, Vol. 77, No. 4, 20.02.2013, p. 639-646.

Research output: Contribution to journalArticle

Ash, Peter E A ; Bieniek, Kevin F. ; Gendron, Tania D ; Caulfield, Thomas ; Lin, Wen Lang ; DeJesus-Hernandez, Mariely ; Van Blitterswijk, Marka ; Jansen-West, Karen ; Paul, Joseph W. ; Rademakers, Rosa V ; Boylan, Kevin B. ; Dickson, Dennis W ; Petrucelli, Leonard. / Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS. In: Neuron. 2013 ; Vol. 77, No. 4. pp. 639-646.
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