A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis

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 role...

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Veröffentlicht in:	Nature neuroscience 2020-03, Vol.23 (3), p.386-397
Hauptverfasser:	Rodriguez, Caitlin M., Wright, Shannon E., Kearse, Michael G., Haenfler, Jill M., Flores, Brittany N., Liu, Yu, Ifrim, Marius F., Glineburg, Mary R., Krans, Amy, Jafar-Nejad, Paymaan, Sutton, Michael A., Bassell, Gary J., Parent, Jack M., Rigo, Frank, Barmada, Sami J., Todd, Peter K.
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Sprache:	eng
Schlagworte:	631/337/574 631/378/1689/2608 631/378/1689/364 631/378/2583 631/45/500 Animal Genetics and Genomics Animals Antisense oligonucleotides Ataxia Behavioral Sciences Biological Techniques Biomedical and Life Sciences Biomedicine Cell Line Cell Survival - genetics Control DNA Repeat Expansion - genetics Female FMR1 protein Fragile X Mental Retardation Protein - biosynthesis Fragile X Mental Retardation Protein - genetics Fragile X syndrome Fragile X Syndrome - genetics Genetic aspects Genetic translation Glutamic acid receptors (metabotropic) Induced Pluripotent Stem Cells Intellectual disabilities Male Mental illness Mice Neurobiology Neurodegeneration Neurons Neurons - metabolism Neurosciences Oligonucleotides Oligonucleotides, Antisense - pharmacology Physiological aspects Protein Biosynthesis Protein synthesis Proteins Rats Rats, Long-Evans Rats, Sprague-Dawley Receptor, Metabotropic Glutamate 5 - biosynthesis Receptor, Metabotropic Glutamate 5 - genetics Receptors RNA Survival Synthesis Toxicity Translation Tremor Trinucleotide Repeats - genetics
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creator	Rodriguez, Caitlin M. Wright, Shannon E. Kearse, Michael G. Haenfler, Jill M. Flores, Brittany N. Liu, Yu Ifrim, Marius F. Glineburg, Mary R. Krans, Amy Jafar-Nejad, Paymaan Sutton, Michael A. Bassell, Gary J. Parent, Jack M. Rigo, Frank Barmada, Sami J. Todd, Peter K.
description	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. Rodriguez et al. define a native role for RAN translation and CGG repeats in regulating mGluR-dependent fragile X protein (FMRP) synthesis. RAN-blocking antisense oligonucleotides increase FMRP and improve survival of neurons from patients with repeat expansions.
doi_str_mv	10.1038/s41593-020-0590-1
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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. 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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. Rodriguez et al. define a native role for RAN translation and CGG repeats in regulating mGluR-dependent fragile X protein (FMRP) synthesis. 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genetics</subject><subject>Genetic aspects</subject><subject>Genetic translation</subject><subject>Glutamic acid receptors (metabotropic)</subject><subject>Induced Pluripotent Stem Cells</subject><subject>Intellectual disabilities</subject><subject>Male</subject><subject>Mental illness</subject><subject>Mice</subject><subject>Neurobiology</subject><subject>Neurodegeneration</subject><subject>Neurons</subject><subject>Neurons - metabolism</subject><subject>Neurosciences</subject><subject>Oligonucleotides</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><subject>Physiological aspects</subject><subject>Protein Biosynthesis</subject><subject>Protein synthesis</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Long-Evans</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptor, Metabotropic Glutamate 5 - biosynthesis</subject><subject>Receptor, Metabotropic Glutamate 5 - genetics</subject><subject>Receptors</subject><subject>RNA</subject><subject>Survival</subject><subject>Synthesis</subject><subject>Toxicity</subject><subject>Translation</subject><subject>Tremor</subject><subject>Trinucleotide Repeats - 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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. 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identifier	ISSN: 1097-6256
ispartof	Nature neuroscience, 2020-03, Vol.23 (3), p.386-397
issn	1097-6256 1546-1726 1546-1726
language	eng
recordid	cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7668390
source	MEDLINE; Springer Nature - Complete Springer Journals; Nature
subjects	631/337/574 631/378/1689/2608 631/378/1689/364 631/378/2583 631/45/500 Animal Genetics and Genomics Animals Antisense oligonucleotides Ataxia Behavioral Sciences Biological Techniques Biomedical and Life Sciences Biomedicine Cell Line Cell Survival - genetics Control DNA Repeat Expansion - genetics Female FMR1 protein Fragile X Mental Retardation Protein - biosynthesis Fragile X Mental Retardation Protein - genetics Fragile X syndrome Fragile X Syndrome - genetics Genetic aspects Genetic translation Glutamic acid receptors (metabotropic) Induced Pluripotent Stem Cells Intellectual disabilities Male Mental illness Mice Neurobiology Neurodegeneration Neurons Neurons - metabolism Neurosciences Oligonucleotides Oligonucleotides, Antisense - pharmacology Physiological aspects Protein Biosynthesis Protein synthesis Proteins Rats Rats, Long-Evans Rats, Sprague-Dawley Receptor, Metabotropic Glutamate 5 - biosynthesis Receptor, Metabotropic Glutamate 5 - genetics Receptors RNA Survival Synthesis Toxicity Translation Tremor Trinucleotide Repeats - genetics
title	A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis
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