Abstract
Amyloid precursor protein (APP) regulates neuronal synapse function, and its cleavage product Abeta is linked to Alzheimer's disease. Here, we present evidence that the RNA-binding proteins (RBPs) heterogeneous nuclear ribonucleoprotein (hnRNP) C and fragile X mental retardation protein (FMRP) associate with the same APP mRNA coding region element, and they influence APP translation competitively and in opposite directions. Silencing hnRNP C increased FMRP binding to APP mRNA and repressed APP translation, whereas silencing FMRP enhanced hnRNP C binding and promoted translation. Repression of APP translation was linked to colocalization of FMRP and tagged APP RNA within processing bodies; this colocalization was abrogated by hnRNP C overexpression or FMRP silencing. Our findings indicate that FMRP represses translation by recruiting APP mRNA to processing bodies, whereas hnRNP C promotes APP translation by displacing FMRP, thereby relieving the translational block.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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3' Untranslated Regions
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Amyloid beta-Protein Precursor / biosynthesis*
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Amyloid beta-Protein Precursor / genetics*
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Animals
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Base Sequence
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Binding, Competitive
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Cell Line
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Cytoplasmic Structures / metabolism
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Fragile X Mental Retardation Protein / genetics
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Fragile X Mental Retardation Protein / metabolism*
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Genes, Reporter
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Green Fluorescent Proteins / genetics
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Heterogeneous-Nuclear Ribonucleoprotein Group C / metabolism*
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Humans
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In Vitro Techniques
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Mice
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Mice, Knockout
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Models, Biological
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Molecular Sequence Data
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Neurons / metabolism*
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Protein Biosynthesis
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RNA, Messenger / genetics*
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RNA, Messenger / metabolism*
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RNA, Small Interfering / genetics
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Recombinant Proteins / genetics
Substances
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3' Untranslated Regions
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Amyloid beta-Protein Precursor
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FMR1 protein, human
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Fmr1 protein, mouse
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Heterogeneous-Nuclear Ribonucleoprotein Group C
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RNA, Messenger
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RNA, Small Interfering
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Recombinant Proteins
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enhanced green fluorescent protein
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Fragile X Mental Retardation Protein
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Green Fluorescent Proteins