microRNA-34a (miRNA-34a) mediated down-regulation of the post-synaptic cytoskeletal element SHANK3 in sporadic Alzheimer’s disease (AD)
- 1LSU Health Sciences Center New Orleans, United States
Integrating a combination of bioinformatics, microRNA microfluidic arrays, ELISA analysis, LED Northern and transfection-luciferase reporter assay data using human neuronal-glial (HNG) cells in primary culture we have discovered a set of up-regulated microRNAs (miRNAs) linked to a small family of down-regulated messenger RNAs (mRNAs) within the superior temporal lobe neocortex (Brodman A22) of sporadic Alzheimer’s disease (AD) brain. At the level of mRNA abundance, the expression of a significant number of human brain genes found to be down-regulated in sporadic AD neocortex appears to be due to the increased abundance of a several brain-abundant inducible miRNAs. These up-regulated miRNAs – including, prominently, miRNA-34a – have complimentary RNA sequences in the 3′ untranslated-region (3′-UTR) of their target-mRNAs that results in the pathological down-regulation in the expression of important brain genes. An up-regulated microRNA-34a, already implicated in age-related inflammatory-neurodegeneration - appears to down-regulate key mRNA targets involved in synaptogenesis and synaptic-structure, distinguishing neuronal deficits associated with AD neuropathology. One significantly down-regulated post-synaptic element in AD is the proline-rich SH3 and multiple-ankyrin-repeat domain SHANK3 protein. Bioinformatics, microRNA array analysis and SHANK3-mRNA-3’UTR luciferase-reporter assay confirmed the importance of miRNA-34a in the regulation of SHANK3 expression in HNG cells. This paper reports on recent studies of a miRNA-34a-up-regulation coupled to SHANK3 mRNA down-regulation in sporadic AD superior-temporal lobe compared to age-matched controls. These findings further support our hypothesis of an altered miRNA-mRNA coupled signaling network in AD, much of which is supported, and here reviewed, by recently reported experimental-findings in the scientific literature.
Keywords: age-related macular degeneration, Alzheimer's disease, microRNA-mRNA linking, miRNA-mRNA signaling, linking and integration, Phagocytosis, neurotrophic signaling, inflammatory neurodegeneration
Received: 05 Sep 2018;
Accepted: 10 Jan 2019.
Edited by:Patrice E. Fort, Michigan Medicine, University of Michigan, United States
Reviewed by:Xuping Li, Houston Methodist Research Institute, United States
Cláudia Guimas Almeida, New University of Lisbon, Portugal
Copyright: © 2019 Zhao, Jaber, LeBeauf, Scharfman and Lukiw. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Walter J. Lukiw, LSU Health Sciences Center New Orleans, New Orleans, United States, firstname.lastname@example.org