Dataset Information

Novel upregulation of amyloid-? precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5'-untranslated region: Implications in Alzheimer's disease.

ABSTRACT: In addition to the devastating symptoms of dementia, Alzheimer's disease (AD) is characterized by accumulation of the processing products of the amyloid-? (A?) peptide precursor protein (APP). APP's non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~?20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3'-untranslated region (UTR) sequence. By contrast, we report a novel activity of miR-346: specifically, that it targets the APP mRNA 5'-UTR to upregulate APP translation and A? production. This upregulation is reduced but not eliminated by knockdown of argonaute 2. The target site for miR-346 overlaps with active sites for an iron-responsive element (IRE) and an interleukin-1 (IL-1) acute box element. IREs interact with iron response protein1 (IRP1), an iron-dependent translational repressor. In primary human brain cultures, miR-346 activity required chelation of Fe. In addition, miR-346 levels are altered in late-Braak stage AD. Thus, miR-346 plays a role in upregulation of APP in the CNS and participates in maintaining APP regulation of Fe, which is disrupted in late stages of AD. Further work will be necessary to integrate other metals, and IL-1 into the Fe-miR-346 activity network. We, thus, propose a "FeAR" (Fe, APP, RNA) nexus in the APP 5'-UTR that includes an overlapping miR-346-binding site and the APP IRE. When a "healthy FeAR" exists, activities of miR-346 and IRP/Fe interact to maintain APP homeostasis. Disruption of an element that targets the FeAR nexus would lead to pathogenic disruption of APP translation and protein production.

SUBMITTER: Long JM

PROVIDER: S-EPMC6514885 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5'-untranslated region: Implications in Alzheimer's disease.

Long Justin M JM Maloney Bryan B Rogers Jack T JT Lahiri Debomoy K DK

Molecular psychiatry 20181123 3

In addition to the devastating symptoms of dementia, Alzheimer's disease (AD) is characterized by accumulation of the processing products of the amyloid-β (Aβ) peptide precursor protein (APP). APP's non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~ 20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3'-untranslated region (UTR) sequence. By ...[more]

PMID: 30470799

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Project description:Gangliosides are important players for controlling neuronal function and are directly involved in AD pathology. They are among the most potent stimulators of A? production, are enriched in amyloid plaques and bind amyloid beta (A?). However, the molecular mechanisms linking gangliosides with AD are unknown. Here we identified the previously unknown function of the amyloid precursor protein (APP), specifically its cleavage products A? and the APP intracellular domain (AICD), of regulating GD3-synthase (GD3S). Since GD3S is the key enzyme converting a- to b-series gangliosides, it therefore plays a major role in controlling the levels of major brain gangliosides. This regulation occurs by two separate and additive mechanisms. The first mechanism directly targets the enzymatic activity of GD3S: Upon binding of A? to the ganglioside GM3, the immediate substrate of the GD3S, enzymatic turnover of GM3 by GD3S was strongly reduced. The second mechanism targets GD3S expression. APP cleavage results, in addition to A? release, in the release of AICD, a known candidate for gene transcriptional regulation. AICD strongly down regulated GD3S transcription and knock-in of an AICD deletion mutant of APP in vivo, or knock-down of Fe65 in neuroblastoma cells, was sufficient to abrogate normal GD3S functionality. Equally, knock-out of the presenilin genes, presenilin 1 and presenilin 2, essential for A? and AICD production, or of APP itself, increased GD3S activity and expression and consequently resulted in a major shift of a- to b-series gangliosides. In addition to GD3S regulation by APP processing, gangliosides in turn altered APP cleavage. GM3 decreased, whereas the ganglioside GD3, the GD3S product, increased A? production, resulting in a regulatory feedback cycle, directly linking ganglioside metabolism with APP processing and A? generation. A central aspect of this homeostatic control is the reduction of GD3S activity via an A?-GM3 complex and AICD-mediated repression of GD3S transcription.

Dataset Information

Novel upregulation of amyloid-? precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5'-untranslated region: Implications in Alzheimer's disease.

Publications

Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5'-untranslated region: Implications in Alzheimer's disease.

Similar Datasets

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