miR-126 contributes to Parkinson's disease by dysregulating the insulin-like growth factor/phosphoinositide 3-kinase signaling

Abstract

Dopamine (DA) neurons in sporadic Parkinson disease (PD) display dysregulated gene expression networks and signaling pathways that are implicated in PD pathogenesis. Micro (mi)RNAs are regulators of gene expression, which could be involved in neurodegenerative diseases. We determined the miRNA profiles in laser microdissected DA neurons from postmortem sporadic PD patients’ brains and age-matched controls. DA neurons had a distinctive miRNA signature and a set of miRNAs was dysregulated in PD. Bioinformatics analysis provided evidence for correlations of miRNAs with signaling pathways relevant to PD, including an association of miR-126 with insulin/IGF-1/PI3K signaling. In DA neuronal cell systems, enhanced expression of miR-126 impaired IGF-1 signaling and increased vulnerability to the neurotoxin 6-OHDA by downregulating factors in IGF-1/PI3K signaling, including its targets p85β, IRS-1, and SPRED1. Blocking of miR-126 function increased IGF-1 trophism and neuroprotection to 6-OHDA. Our data imply that elevated levels of miR-126 may play a functional role in DA neurons and in PD pathogenesis by downregulating IGF-1/PI3K/AKT signaling and that its inhibition could be a mechanism of neuroprotection.

Alpha-synuclein overexpression negatively regulates insulin receptor substrate 1 by activating mTORC1/S6K1 signaling

“…Recent reports suggest that IRS-2 serine phosphorylation is increased and total IRS-2 level is decreased in a 6-hydroxydopamine (OHDA) PD animal model (Morris et al, 2008), while other studies have shown that total IRS-1 was decreased in a 6-OHDA cell model of PD (Kim et al, 2014). Rosiglitazone, an insulin sensitizer, prevents dopaminergic cell loss induced by chronic mitochondrial permeability transition pore stimulation in the SNc (Schintu et al, 2009).…”

Gene Co-Expression Network Analysis Implicates microRNA Processing in Parkinson’s Disease Pathogenesis

“…Decreased levels of individual miRNAs have been implicated in PD pathogenesis, including miR-133b [17], miR-7 [18], miR-153 [19], miR-433 [20], miR-34b/c [21], miR-126 [22], and miR-155 [23], but most of these findings have been difficult to replicate. In general, miRNA silencing plays a critical role in brain morphogenesis and differentiation of the substantia nigra [17,24,25], as well as in PD implicated pathways such as the ubiquitin-proteasome system, autophagy, apoptosis, and mitochondrial function [26].…”

Role of genomics in translational research for Parkinson’s disease

“…Targets Changes miR-133b [83] Survival of dopaminergic neurons Pitx3 Down-regulated in PD brain miR-433 [84] Regulates the expression of a-synuclein FGF20 -miR-7 [85] Regulate oxidative stress and cell death a-Synuclein -miR-153 and miR-7 [86] Regulates the expression of a-synuclein a-Synuclein -miR-184 and let-7 [87] Regulate dopaminergic neurons survival and activity DP and E2F1 Influence by mutant LRRK2 miR-34b/c [88] Modulating expression of DJ1 and Parkin Unknown Down-regulated in PD brain miR-205 [89] Suppressed the expression of LRRK2 LRRK2 Down-regulated in PD brain miR-126 [90] Suppressed the IGF-1/PI3K signals p86b, IRS-1 and SPRED1 -miR-1, miR-22, miR-29 [91] Biomarkers for PD in blood -Down-regulated in PD blood miR-1826, miR-450b-3p, miR-626, miR-505 [92] Biomarkers for PD in plasma -Up-regulated in PD Plasma 356 for miR-433 on the FGF20 gene has been associated with PD, and 357 that increased FGF20 up-regulate the aS level [85]. Furthermore, 358 miR-7, which was deceased in a PD mouse model, has been shown 359 to down-regulate the expression of aS [86].…”

“…In particular, allele- of the toxic protein is reduced [82,83]. 335 More recently, the evidence is accumulating to support a rele-336 vance of miRNA in the pathogenesis in PD [84][85][86][87][88][89][90][91][92][93] (Table 3) [84]. It was also showed that a mutation of the binding site Table 3 Involvement of miRNAs in PD pathology.…”