HOTAIR drives autophagy in midbrain dopaminergic neurons in the substantia nigra compacta in a mouse model of Parkinson’s disease by elevating NPTX2 via miR-221-3p binding

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive cell loss, largely confined to mesencephalic dopamine neurons of the substantia nigra. This study investigated the functional relevance of the HOX transcript antisense intergenic RNA (HOTAIR)/microRNA-221-3 (miR-221-3p)/neuronal pentraxin II (NPTX2) axis in the process of dopaminergic neuron autophagy using PD mouse models. The PD mouse models were established by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP), while PD cell model was constructed by pretreatment with 1-methyl-4-phenylpyridinium (MPP +). The expression of HOTAIR was then examined using RT-qPCR. In addition, the interactions between HOTAIR, miR-221-3p, and NPTX2 were detected through RIP and dual-luciferase reporter gene assays. CCK-8 assay was performed to measure cell viability, and the expression of autophagy-related genes was determined using Western blot analysis. HOTAIR was found to be significantly expressed in the substantia nigra compact tissues and MN9D cells following PD modeling. HOTAIR could bind to miR-221-3p and elevate the NPTX2 expression, which resulted in diminished cell viability and enhanced autophagy of dopaminergic neurons both in vitro and in vivo. In summary, down-regulation of HOTAIR could potentially inhibit the autophagy of dopaminergic neurons in the substantia nigra compacta in a mouse model of PD, thus saving the demise of dopaminergic neurons. .

DNA methylation and regulation of gene expression: Guardian of our health

“…Significant changes in the ratio of vitamin intake were found to affect the CpG island methylation pattern in the loci of DNMT1, DNMT3A and DNMT3B, consequently leading to increased expression of the methyltransferases [ 29 ]. Even levels of miRNAs like that of miR-133 (linked to muscle and cardiac tissue metabolism and certain kinds of cancer) [ 54 , 58 , 65 , 85 , 86 , 98 , 101 ] and miR-221 (linked to oncogenesis) [ 10 , 25 , 50 , 56 , 60 , 71 , 79 , 90 , 96 , 100 ] changed in response to a skewed ratio of intake of the two vitamins. Other than sub or supra-optimal levels of folate or B12 intake, vitamin C or ascorbic acid consumption during the perinatal period also seems significant [ 19 ].…”

Differential gene expression in the interactome of the Human Dopamine transporter in the context of Parkinson’s disease

“…Regarding the to miRNA – target interactions (MTIs) in interatome hDAT and are deregulated in PD, in a previous study of Parkinson’s patients that aimed to the Identification of Novel Biomarkers in PD was carried out as follows approach: i)experimentally supported databases with experimentally verified and ii) different prediction algorithms[13], which allows obtaining the following resulted miRNAs : miR-126-5p, hsa-miR-29b-3p, and hsa-miR-301a-3p which are also described in the present study about this miRNAs and interaction with mRNA previously described that miR-126-5p interaction with CAMK2A [53], EPS15 [53, 54], NEDD4 and SNCA[56], the hsa-miR-29b-3p interaction with EPS15 [57], CDH1 [58], GPR37[59] and the hsa-miR-301a-3p interaction with CSK[60] and EPS15[61] which are also part of hDAT interactome, which although we found miRNAs that interacted with multiple mRNAs of hDAT interactome proteins, which presented altered expression in PD vs controls, we did not find any type of relationship either in the number of miRNAs per target of the interactome, or in the combined estimate of rate of miRNA change and the combined estimate of rate of change in hDAT interactome mRNAs.…”

Diagnostic Values of miR-221-3p in Serum and Cerebrospinal Fluid for Post-Stroke Depression and Analysis of Risk Factors

“…For instance, in cerebral ischemic stroke, it regulates endothelial cell functions by regulating the signal transduction of PTEN-PI3K-AKT pathway. In the mouse model of Parkinson's disease, it is regulated by HOTAIR and then specifically regulates downstream factor NPTX2, further regulating the proliferation and autophagy of dopaminergic neurons in the substantia nigra pars compacta (21,22). Additionally, it remarkably upregulates in liver cancer (23), gastric cancer (24) and acute lung injury (25).…”