Open AccessA native function for RAN translation and CGG repeats in regulating fragile X protein synthesis
Author(s) -
Caitlin M. Rodriguez,
Shan E. Wright,
Michael G. Kearse,
Jill M. Haenfler,
Brittany Flores,
Yu Liu,
Marius F. Ifrim,
M. Rebecca Glineburg,
Amy Krans,
Paymaan JafarNejad,
Michael A. Sutton,
Gary J. Bassell,
Jack M. Parent,
Frank Rigo,
Sami J. Barmada,
Peter K. Todd
Publication year - 2020
Publication title -
nature neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 13.403
H-Index - 422
eISSN - 1546-1726
pISSN - 1097-6256
DOI - 10.1038/s41593-020-0590-1
Subject(s) - ran , fragile x syndrome , fmr1 , biology , translation (biology) , protein biosynthesis , eukaryotic translation , open reading frame , microbiology and biotechnology , genetics , messenger rna , fragile x , gene , peptide sequence
Repeat-associated non-AUG-initiated translation of expanded CGG repeats (CGG RAN) from the FMR1 5'-leader produces toxic proteins that contribute to neurodegeneration in fragile X-associated tremor/ataxia syndrome. Here we describe how unexpanded CGG repeats and their translation play conserved roles in regulating fragile X protein (FMRP) synthesis. In neurons, CGG RAN acts as an inhibitory upstream open reading frame to suppress basal FMRP production. Activation of mGluR5 receptors enhances FMRP synthesis. This enhancement requires both the CGG repeat and CGG RAN initiation sites. Using non-cleaving antisense oligonucleotides (ASOs), we selectively blocked CGG RAN. This ASO blockade enhanced endogenous FMRP expression in human neurons. In human and rodent neurons, CGG RAN-blocking ASOs suppressed repeat toxicity and prolonged survival. These findings delineate a native function for CGG repeats and RAN translation in regulating basal and activity-dependent FMRP synthesis, and they demonstrate the therapeutic potential of modulating CGG RAN translation in fragile X-associated disorders.