MiR-128-3p - a gray eminence of the human central nervous system

Abstract

MicroRNA-128-3p (miR-128-3p) is a versatile molecule with multiple functions in the physiopathology of the human central nervous system. Perturbations of miR-128-3p, which is enriched in the brain, contribute to a plethora of neurodegenerative disorders, brain injuries, and malignancies, as this miRNA is a crucial regulator of gene expression in the brain, playing an essential role in the maintenance and function of cells stemming from neuronal lineage. However, the differential expression of miR-128-3p in pathologies underscores the importance of the balance between its high and low levels. Significantly, numerous reports pointed to miR-128-3p as one of the most depleted in glioblastoma, implying it is a critical player in the disease's pathogenesis and thus may serve as a therapeutic agent for this most aggressive form of brain tumor. In this review, we summarize the current knowledge of the diverse roles of miR-128-3p. We focus on its involvement in the neurogenesis and pathophysiology of malignant and neurodegenerative diseases. We also highlight the promising potential of miR-128-3p as an antitumor agent for the future therapy of human cancers, including glioblastoma, and as the linchpin of brain development and function, potentially leading to the development of new therapies for neurological conditions.

Keywords: MT: Non-coding RNAs; brain injuries; brain tumors; central nervous system; glioblastoma; miR-128-3p; microRNA; neurodegenerative disorders.

Graphical abstract

Figure 1

The milestones of microRNA discovery, including miR-128-3p

Figure 2

The expression of mature miR-128-3p, miR-128-1-5p, and miR-128-2-5p across normal human tissues and organs Scatter plots of miR-128-3p (A), miR-128-1-5p (B), and miR-128-2-5p (C) expression (shown as log2 RPMM; reads per million mapped reads) in human tissues and organs. The scatterplots generated by GraphPad Prism (ver. 10.0) using the datasets obtained from Human microRNA Tissue Atlas (https://ccb-web.cs.uni-saarland.de/tissueatlas2), accessed on December 2023). The number of specimens: adipocyte n = 5, adrenal gland n = 2, artery n = 6, bladder n = 4, bone n = 5, bowel n = 16, brain n = 39, diaphragm n = 1, esophagus n = 5, gallbladder n = 2, glandular breast tissue n = 1, heart n = 14, kidney n = 7, liver n = 7, lung n = 9, lymph node n = 3, muscle n = 4, nerve n = 7, pancreas n = 6, pleurae n = 4, prostate n = 1, salivary gland n = 1, sclera n = 1, skin n = 6, spinal cord n = 2, spleen n = 4, stomach n = 6, submandibular gland n = 2, testis n = 4, thyroid n = 4, tongue n = 2, trachea n = 2, urethra n = 1, uterus n = 1, vein n = 4.

Figure 3

The canonical pathway of miR-128 biogenesis The hsa-MIR128-1 gene resides within an intron of the R3HDM1 protein-coding gene on chromosome 2 (q21.3), whereas the hsa-MIR128-2 gene is located on chromosome 3 (p22.3) within an intron of the ARPP-21 protein-coding gene. These genomic loci undergo RNA Pol II/III transcription, yielding an extended primary transcript (pri-microRNA). Subsequently, the microRNA complex, composed of the endoribonuclease DROSHA and the RNA-binding protein DGCR8, cleaves these pri-microRNAs in the nucleus, generating precursor microRNAs (pre-microRNAs). The exportin-5 (XPO5)/Ran-guanosine triphosphate (Ran-GTP) complex recognizes the pre-microRNA, facilitating its translocation from the nucleus to the cytoplasm. Once in the cytoplasm, the DICER complex further processes the pre-microRNA, producing a short microRNA duplex. The duplex undergoes unwinding, with one strand becoming the mature microRNA and the other being degraded. It is important to note that the hsa-MIR128 gene produces two mature microRNA variants, miR-128-3p, and miR-128-5p, resulting from this processing pathway. Notably, both loci ultimately yield an identical mature miR-128-3p upon DICER processing.

Figure 4

The expression of mature miR-128-3p, miR-128-1-5p, and miR-128-2-5p in brain structures from healthy donors Scatter plots of miR-128-3p (A), miR-128-1-5p (B), and miR-128-2-5p (C) expression (shown as log2 RPMM; reads per million mapped reads) in human brain structures generated by GraphPad Prism (ver. 10.0) using the datasets obtained from Human microRNA Tissue Atlas (https://ccb-web.cs.uni-saarland.de/tissueatlas2, accessed on December 2023). The number of specimens: arachnoid mater n = 2, cerebellum n = 2, dura mater n = 3, frontal lobe n = 3, gray matter n = 3, hippocampus n = 1, hypothalamus n = 1, medulla oblongata n = 1, nucleus caudatus n = 3, occipital lobe n = 3, parietal lobe n = 1, pituitary gland n = 3, substantia nigra n = 2, temporal lobe n = 3, thalamus n = 3, white matter n = 4.

Figure 5

The implications of miR-128-3p for the brain function The boxes summarize the crucial roles of miR-128-3p in several aspects of CNS function, such as differentiation and maintenance of neurons, pathogenesis of brain tumors, and neurological diseases.