@article{78db777dd7ad4ee983160b4182dcf35e,
title = "Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS",
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",
author = "Ash, \{Peter E.A.\} and Bieniek, \{Kevin F.\} and Gendron, \{Tania F.\} and Thomas Caulfield and Lin, \{Wen Lang\} and Mariely DeJesus-Hernandez and \{Van Blitterswijk\}, \{Marka M.\} and Karen Jansen-West and Paul, \{Joseph W.\} and Rosa Rademakers and Boylan, \{Kevin B.\} and Dickson, \{Dennis W.\} and Leonard Petrucelli",
note = "Funding Information: We are grateful to all patients, family members, and caregivers who agreed to brain donation, without which these studies would have been impossible. We also acknowledge expert technical assistance of Linda Rousseau, Virginia Phillips, and Monica Castanedes-Casey for histology and John Gonzalez, Beth Marten, Pamela Desaro, and Amelia Johnston for brain banking. This work was supported by Mayo Clinic Foundation, National Institutes of Health/National Institute on Aging (R01 AG026251 [L.P., R.R.], P01 AG003949 [D.W.D.], P50 AG016574 [D.W.D., R.R.]), National Institutes of Health/National Institute of Neurological Disorders and Stroke (R21 NS074121-01 [T.F.G., K.B.B.], R01 NS080882 [R.R.], R01 NS063964 [L.P.], R01 NS077402 [L.P.], P50 NS72187 [D.W.D., R.R.]), National Institute of Environmental Health Services (R01 ES20395 [L.P.]), Amyotrophic Lateral Sclerosis Association (K.B.B., L.P.), ALS Therapy Alliance (R.R.), and Department of Defense (W81XWH-10-1-0512-1 [L.P.], W81XWH-09-1-0315AL093108 [L.P.]). R.R. and M.D.-H. have a patent on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene. ",
year = "2013",
month = feb,
day = "20",
doi = "10.1016/j.neuron.2013.02.004",
language = "English (US)",
volume = "77",
pages = "639--646",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "4",
}