Background/Aims: Parkinson’s disease (PD) is a frequently occurring condition that resulted from the loss of midbrain neurons, which synthesize the neurotransmitter dopamine. In this study, we established mouse models of PD to investigate the expression of microRNA-128 (miR-128) and mechanism through which it affects apoptosis of dopamine (DA) neurons and the expression of excitatory amino acid transporter 4 (EAAT4) via binding to axis inhibition protein 1 (AXIN1). Methods: Gene expression microarray analysis was performed to screen differentially expressed miRNAs that are associated with PD. The targeting relationship between miR-128 and AXIN1 was verified via a bioinformatics prediction and dual-luciferase reporter gene assay. After separation, DA neurons were subjected to a series of inhibitors, activators and shRNAs to validate the mechanisms of miR-128 in controlling of AXIN1 in PD. Positive protein expression of AXIN1 and EAAT4 in DA neurons was determined using immunocytochemistry. miR-128 expression and the mRNA and protein levels of AXIN1 and EAAT4 were evaluated via RT-qPCR and Western blot analysis, respectively. DA neuron apoptosis was evaluated using TUNEL staining. Results: We identified AXIN1 as an upregulated gene in PD based on the microarray data of GSE7621. AXIN1 was targeted and negatively mediated by miR-128. In the DA neurons, upregulated miR-128 expression or sh-AXIN1 increased the positive expression rate of EAAT4 together with mRNA and protein levels, but decreased the mRNA and protein levels of AXIN1, apoptosis rate along with the positive expression rate of AXIN1; however, the opposite trend was found in response to transfection with miR-128 inhibitors. Conclusion: Evidence from experimental models revealed that miR-128 might reduce apoptosis of DA neurons while increasing the expression of EAAT4 which might be related to the downregulation of AXIN1. Thus, miR-128 may serve as a potential target for the treatment of PD.

Brain size and cognitive skills are the most dramatically changed traits in humans during evolution and yet the genetic mechanisms underlying these human-specific changes remain elusive. Here, we successfully generated 11 transgenic rhesus monkeys (8 first-generation and 3 second-generation) carrying human copies of MCPH1, an important gene for brain development and brain evolution. Brain-image and tissue-section analyses indicated an altered pattern of neural-cell differentiation, resulting in a delayed neuronal maturation and neural-fiber myelination of the transgenic monkeys, similar to the known evolutionary change of developmental delay (neoteny) in humans. Further brain-transcriptome and tissue-section analyses of major developmental stages showed a marked human-like expression delay of neuron differentiation and synaptic-signaling genes, providing a molecular explanation for the observed brain-developmental delay of the transgenic monkeys. More importantly, the transgenic monkeys exhibited better short-term memory and shorter reaction time compared with the wild-type controls in the delayed-matching-to-sample task. The presented data represent the first attempt to experimentally interrogate the genetic basis of human brain origin using a transgenic monkey model and it values the use of non-human primates in understanding unique human traits.

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Purpose To explore the involvement of N 6 -methyladenosine (m 6 A) modification in circular RNAs (circRNAs) and relevant methyltransferases in the lesion of lens epithelium cells (LECs) under the circumstances of age-related cataract (ARC). Methods LECs were collected from normal subjects and patients with cortical type of ARC (ARCC). M 6 A-tagged circRNAs and circRNAs expression were analyzed by m 6 A-modified RNA immunoprecipitation sequencing (m 6 A-RIP-seq) and RNA sequencing (RNA-seq). Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to predict possible functions of the m 6 A-circRNAs. Expression of m 6 A-related methyltransferase and demethytransferase was measured by quantitative real-time polymerase chain reaction. Expression and location of AlkB homolog 5 RNA demethylase (ALKBH5), a key component of m 6 A demethytransferase, were determined by Western blot and immunostaining. Results All 4646 m 6 A peaks within circRNAs had different abundances, with 2472 enriched and 2174 subdued. The level of m 6 A abundance in total circRNAs was decreased in the LECs from ARCCs in comparison with the controls. We also found that the expression of highly m6A-tagged circRNAs was mostly decreased in comparison with non-m 6 A-tagged circRNAs. The bioinformatics analysis predicted the potential functions of m 6 A modified circRNAs and the relevant pathways that may be associated with m 6 A modified circRNAs. Among five major methyltransferases, ALKBH5 was significantly upregulated in LECs of ARCCs. Conclusions Our data provided novel evidence regarding the involvement of circRNAs m 6 A modifications in ARC. The altered expression of methyltransferases in lens tissue might selectively change the epigenetic profile of lens genome through regulating genes that host the circRNAs, thus enhance the susceptibility to ARC. The results might provide a new insight in the molecular target of ARC pathogenesis.

The role and mechanism of collagen type VI alpha 6 (COL6A6) on tumor growth and metastasis in pituitary adenoma (PA) was determined. COL6A6 was downregulated in PA tissues and cell lines, which was negatively associated with the expression of prolyl-4-hydroxylase alpha polypeptide III (P4HA3) in the progression of PA. Overexpression of COL6A6 significantly suppressed tumor growth and metastasis capacity in PA. In addition, P4HA3 worked as the upstream of the PI3K-Akt pathway to alleviate the antitumor activity of COL6A6 on the growth and metastasis of both AtT-20 and HP75 cells. Furthermore, the inhibitory effect of COL6A6 on cell proliferation, migration and invasion, and epithelial-mesenchymal transition (EMT) was reversed by P4HA3 overexpression or activation of the PI3K-Akt pathway induced by IGF-1 addition, which provided a new biomarker for clinical PA treatment.