Neuronal ELAVL proteins utilize AUF-1 as a co-partner to induce neuron-specific alternative splicing of APP

Aβ peptide that accumulates in Alzheimer’s disease brain, derives from proteolytic processing of the amyloid precursor protein (APP) that exists in three main isoforms derived by alternative splicing. The isoform APP695, lacking exons 7 and 8, is predominately expressed in neurons and abnormal neuro...

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Bibliographic Details
Published in:Scientific reports 2017-03, Vol.7 (1), p.44507-44507, Article 44507
Main Authors: Fragkouli, Apostolia, Koukouraki, Pelagia, Vlachos, Ioannis S., Paraskevopoulou, Maria D., Hatzigeorgiou, Artemis G., Doxakis, Epaminondas
Format: Article
Language:English
Subjects:
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631/337/1645/1792
631/378/1689/364
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Alternative splicing
Alzheimer's disease
Amyloid precursor protein
Conserved sequence
Eukaryotes
Exons
Humanities and Social Sciences
Isoforms
mRNA
mRNA processing
multidisciplinary
Neurodegenerative diseases
Post-transcription
Proteolysis
Science
Splicing factors
Upstream
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Summary:Aβ peptide that accumulates in Alzheimer’s disease brain, derives from proteolytic processing of the amyloid precursor protein (APP) that exists in three main isoforms derived by alternative splicing. The isoform APP695, lacking exons 7 and 8, is predominately expressed in neurons and abnormal neuronal splicing of APP has been observed in the brain of patients with Alzheimer’s disease. Herein, we demonstrate that expression of the neuronal members of the ELAVL protein family (nELAVLs) correlate with APP695 levels in vitro and in vivo . Moreover, we provide evidence that nELAVLs regulate the production of APP695; by using a series of reporters we show that concurrent binding of nELAVLs to sequences located both upstream and downstream of exon 7 is required for its skipping, whereas nELAVL-binding to a highly conserved U-rich sequence upstream of exon 8, is sufficient for its exclusion. Finally, we report that nELAVLs block APP exon 7 or 8 definition by reducing the binding of the essential splicing factor U2AF65, an effect facilitated by the concurrent binding of AUF-1. Our study provides new insights into the regulation of APP pre-mRNA processing, supports the role for nELAVLs as neuron-specific splicing regulators and reveals a novel function of AUF1 in alternative splicing.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep44507