MiR-126 Regulates Growth Factor Activities and Vulnerability to Toxic Insult in Neurons

Abstract

Dysfunction of growth factor (GF) activities contributes to the decline and death of neurons during aging and in neurodegenerative diseases. In addition, neurons become more resistant to GF signaling with age. Micro (mi)RNAs are posttranscriptional regulators of gene expression that may be crucial to age- and disease-related changes in GF functions. miR-126 is involved in regulating Insulin/IGF-1/PI3K/AKT and ERK signaling and we recently demonstrated a functional role of miR-126 in dopamine neuronal cell survival in models of Parkinson’s disease (PD)-associated toxicity. Here, we show that elevated levels of miR-126 increase neuronal vulnerability to ubiquitous toxicity mediated by staurosporine (STS) or Alzheimer’s disease (AD)-associated amyloid beta 1-42 peptides (Aβ1-42). The neuroprotective factors IGF-1, NGF, BDNF, and soluble amyloid precursor protein α (sAPPα) could diminish but not abrogate the toxic effects of miR-126. In miR-126 overexpressing neurons derived from Tg6799 familial AD model mice, we observed an increase in Aβ1-42 toxicity but, surprisingly, both Aβ1-42 and miR-126 promoted neurite sprouting. Pathway analysis revealed that miR-126 overexpression downregulated elements in the GF/PI3K/AKT and ERK signaling cascades, including AKT, GSK-3β, ERK, their phosphorylation, and the miR-126 targets IRS-1 and PIK3R2. Finally, inhibition of miR-126 was neuroprotective against both STS and Aβ1-42 toxicity. Our data provide evidence for a novel mechanism of regulating GF/PI3K signaling in neurons by miR-126 and suggest that miR-126 may be an important mechanistic link between metabolic dysfunction and neurotoxicity in general, during aging, and in the pathogenesis of specific neurological disorders, including PD and AD.

MicroRNA-126 Reduces Blood-Retina Barrier Breakdown via the Regulation of VCAM-1 and BCL2L11 in Ischemic Retinopathy

“…Our finding provided evidence that miR-126 protected neurons in vivo. Furthermore, although several studies including our previous study have identified that the effects of miR-126 on retinal neovascularization were associated with the Akt signaling pathway [49][50][51] , the current results suggested that miR-126 may also go through the Jak-STAT3 signaling pathway to target Müller cell survival. Also, the reason for our online supplementary data establishing an ischemic cell model with CoCl 2 was that treatment with CoCl 2 stimulated the cells to hypoxia by modulating similar gene and protein expressions as in ischemic states [52] ; this supported our animal results in vitro.…”

“…Müller cells, which produce growth factors including VEGF, contribute to BRB integrity and neuroprotection by maintaining the retinal structure and supporting several types of retinal cells. Many publications have implied that miRNAs were beneficial for neuron growth, whereas the evidence for the effects of miR-126 is missing [46][47][48][49] . Our finding provided evidence that miR-126 protected neurons in vivo.…”

Midbrain dopamine neurons in Parkinson׳s disease exhibit a dysregulated miRNA and target-gene network

“…miR-320 was detected at high levels in pigmented neurons in the SN by in situ hybridization (Nelson et al, 2008), confirming the qRT-PCR data in the current study. As for functional relevance, we could show that miR-126 may play an important role in neurotoxicity and neuroprotection by regulating growth factor/PI3K/AKT and MAPK/ERK signaling (Kim et al, 2014a; Kim et al, 2014h), and preliminary data indicate similar neurotoxic functions for miR-320 as well (unpublished results). Together, these data suggest that these, and other miRNAs, may be functionally involved in aging and neurodegeneration, and therefore, could be therapeutic targets in neurological disorders.…”

“…miRNAs are short non-coding RNAs that regulate gene expression on the pre- or post-transcriptional level (Bartel, 2009), and evidence suggests that these molecules are involved in the pathology of PD (Heman-Ackah et al, 2013; Ma et al, 2013; Sonntag, 2010; Wong and Nass, 2012). We found that human SN DA neurons have a distinctive miRNA expression profile that is dysregulated in PD, and functional analysis of miR-126, which was upregulated in PD DA neurons, unraveled an association of this miRNA with Insulin/IGF-1/PI3K signaling, a pathway that has been implicated in PD (Kim et al, 2014a; Kim et al, 2014h). These data suggested that miRNAs may have functional roles in DA neurons and in the pathogenesis of PD.…”

Interaction between miRNAs and signaling cascades of Wnt pathway in chronic lymphocytic leukemia

“…46,47 Numbers of experiments established that several miRNAs play a very crucial function within Wnt signaling cascade, for example, miR-34a, miR-26a, miR-126, miR-135a, miR-135b, miR-155, miR-21, and miR-29 are among some of the well-studied miRNAs ( Figure 2). 26,[48][49][50][51][52][53][54] miRNAs are known to decrease the expression level of the tumor suppressor gene, resulting in the higher expression of target oncogenes. Conversely, it has also been observed that elevated expression of miRNAs controlling oncogenic protein suppresses the expression level of tumor suppressor genes.…”