MicroRNA-Related Cofilin Abnormality in Alzheimer's Disease

Yao, Jiaqi; Hennessey, Tom; Flynt, Alex S.; Lai, Eric C.; Beal, M. Flint; Lin, Michael

doi:10.1371/journal.pone.0015546

Cited by 89 publications

(70 citation statements)

References 26 publications

(48 reference statements)

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“…2 Indeed, it has been demonstrated that Ab can induce actin/cofilin pathology associated with hyperphosphorylated tau in primary neurons and in vivo. [3][4][5] We recently demonstrated that the scaffolding protein RanBP9 interacts with the cytoplasmic tails of LRP, APP, and BACE1, and functions as a scaffold upon which APP is brought together with BACE1 and LRP. Such interactions of RanBP9 promote the endocytosis of APP and strongly increase BACE1 cleavage of APP to generate Ab in vitro and in vivo.…”

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confidence: 99%

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

et al. 2012

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Neurodegeneration associated with amyloid b (Ab) peptide accumulation, synaptic loss, neuroinflammation, tauopathy, and memory impairments encompass the pathophysiological features of Alzheimer's disease (AD). We previously reported that the scaffolding protein RanBP9, which is overall increased in brains of AD patients, simultaneously promotes Ab generation and focal adhesion disruption by accelerating the endocytosis of amyloid precursor protein (APP) and b1-integrin, respectively. Here, we show that RanBP9 protein levels are increased by fourfold in FAD mutant APP transgenic mice. Accordingly, RanBP9 transgenic mice demonstrate significantly increased synapse loss, neurodegeneration, gliosis, and spatial memory deficits. RanBP9 overexpression promotes apoptosis and potentiates Ab-induced neurotoxicity independent of its capacity to promote Ab generation. Conversely, RanBP9 reduction by siRNA or gene dosage mitigates Ab-induced neurotoxicity. Importantly, RanBP9 activates/dephosphorylates cofilin, a key regulator of actin dynamics and mitochondria-mediated apoptosis, and siRNA knockdown of cofilin abolishes both Ab and RanBP9-induced apoptosis. These findings implicate the RanBP9-cofilin pathway as critical therapeutic targets not only for stemming Ab generation but also antagonizing Ab-induced neurotoxicity. Cell Death and Differentiation (2012) 19, 1413-1423; doi:10.1038/cdd.2012.14; published online 24 February 2012Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulations of the amyloid b (Ab) -peptide and hyperphosphorylated tau in senile plaques and neurofibrillary tangles, respectively. Ab is a neurotoxic peptide derived from b-and g-secretase cleavages of the amyloid precursor protein (APP) and is thought to be a critical early player in AD pathogenesis. 1 In addition to the accumulation of Ab and tau, abnormalities in the actin cytoskeleton are detected earlier during the course of AD and other neurodegenerative diseases. 2 Indeed, it has been demonstrated that Ab can induce actin/cofilin pathology associated with hyperphosphorylated tau in primary neurons and in vivo. [3][4][5] We recently demonstrated that the scaffolding protein RanBP9 interacts with the cytoplasmic tails of LRP, APP, and BACE1, and functions as a scaffold upon which APP is brought together with BACE1 and LRP. Such interactions of RanBP9 promote the endocytosis of APP and strongly increase BACE1 cleavage of APP to generate Ab in vitro and in vivo. 6,7 Conversely, siRNA knockdown of RanBP9 reduces BACE1 cleavage of APP and Ab generation, indicating that endogenous RanBP9 normally functions in this capacity. 6 In addition, a 60-kD proteolytic fragment of RanBP9 is increased by more than sixfold in brains of AD patients, and this fragment potentiates Ab generation via BACE1 processing of APP. 8 In addition to promoting Ab generation by accelerating APP endocytosis, RanBP9 also potently disrupts integrin-dependent focal adhesion signaling and assembly by accelerating b1-integrin and LRP endocytosis. 9 In th...

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confidence: 99%

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

et al. 2012

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“…Therefore loss of miR-29 expression may lead to neuron vulnerability and neurodegeneration. Additional roles for miR-107 in AD pathogenesis are demonstrated by studies in a transgenic mouse model of AD which over-expresses human APP carrying familial AD mutations (Yao et al, 2010). In particular reduced levels of miR-103 or miR-107 are associated with elevated cofilin protein levels and formation of rod-like structures in this AD mouse model.…”

Section: Mirnas Dysregulated In Ad Modulate Bace and Other Targetsmentioning

confidence: 89%

Advances in MicroRNAs and Alzheimer’s Disease Research

Ruberti¹,

Pezzola²,

Barbato³

2011

Alzheimer's Disease Pathogenesis-Core Concepts, Shifting Paradigms and Therapeutic Targets

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“…MiR-103a-3p has been shown to play important roles in cellular processes such as DNA repair, metabolism, cell cycle progression, and cell differentiation (Liu et al 2009;Yang et al 2009;Finnerty et al 2010;Liao and Lonnerdal 2010;Polster et al 2010) and to be dysregulated in multiple diseases (e.g., cancers) and conditions (e.g., diabetes, Alzheimer's disease, etc.) (Roldo et al 2006;Xie et al 2009;Yao et al 2010). To date only a few targets are known for miR-103a-3p.…”

Section: Discussionmentioning

confidence: 99%

“…(Finnerty et al 2010). MiR-103a-3p's dysregulation has been associated with many human diseases including several cancers, Alzheimer's disease, and diabetes (Martello et al 2010;Yao et al 2010;Trajkovski et al 2011).…”

Section: Introductionmentioning

confidence: 99%

MiR-103a-3p targets the 5′ UTR of GPRC5A in pancreatic cells

Zhou

Rigoutsos

2014

RNA

120

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MicroRNAs (miRNAs) are short noncoding RNAs that regulate the expression of their targets in a sequence-dependent manner. For protein-coding transcripts, miRNAs regulate expression levels through binding sites in either the 3 ′ untranslated region (3 ′ UTR) or the amino acid coding sequence (CDS) of the targeted messenger RNA (mRNA). Currently, for the 5 ′ untranslated region (5 ′ UTR) of mRNAs, very few naturally occurring examples exist whereby the targeting miRNA down-regulates the expression of the corresponding mRNA in a seed-dependent manner. Here we describe and characterize two miR-103a-3p target sites in the 5 ′ UTR of GPRC5A, a gene that acts as a tumor suppressor in some cancer contexts and as an ongocene in other cancer contexts. In particular, we show that the interaction of miR-103a-3p with each of these two 5 ′ UTR targets reduces the expression levels of both GPRC5A mRNA and GPRC5A protein in one normal epithelial and two pancreatic cancer cell lines. By ectopically expressing "sponges" that contain instances of the wild-type 5′ UTR targets we also show that we can reduce miR-103a-3p levels and increase GPRC5A mRNA and protein levels. These findings provide some first knowledge on the post-transcriptional regulation of this tumor suppressor/oncogene and present additional evidence for the participation of 5 ′ UTRs in miRNA driven post-transcriptional regulatory control.

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MicroRNA-Related Cofilin Abnormality in Alzheimer's Disease

Cited by 89 publications

References 26 publications

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

Advances in MicroRNAs and Alzheimer’s Disease Research

MiR-103a-3p targets the 5′ UTR of GPRC5A in pancreatic cells

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