microRNAs as neuroregulators, biomarkers and therapeutic agents in neurodegenerative diseases

Abstract

The last decade has experienced the emergence of microRNAs as a key molecular tool for the diagnosis and prognosis of human diseases. Although the focus has mostly been on cancer, neurodegenerative diseases present an exciting, yet less explored, platform for microRNA research. Several studies have highlighted the significance of microRNAs in neurogenesis and neurodegeneration, and pre-clinical studies have shown the potential of microRNAs as biomarkers. Despite this, no bona fide microRNAs have been identified as true diagnostic or prognostic biomarkers for neurodegenerative disease. This is mainly due to the lack of precisely defined patient cohorts and the variability within and between individual cohorts. However, the discovery that microRNAs exist as stable molecules at detectable levels in body fluids has opened up new avenues for microRNAs as potential biomarker candidates. Furthermore, technological developments in microRNA biology have contributed to the possible design of microRNA-mediated disease intervention strategies. The combination of these advancements, with the availability of well-defined longitudinal patient cohort, promises to not only assist in developing invaluable diagnostic tools for clinicians, but also to increase our overall understanding of the underlying heterogeneity of neurodegenerative diseases. In this review, we present a comprehensive overview of the existing knowledge of microRNAs in neurodegeneration and provide a perspective of the applicability of microRNAs as a basis for future therapeutic intervention strategies.

Keywords: Biomarker; Body fluid; Neurodegenerative diseases; Therapeutic agent; Tissue-enriched; microRNA; microRNA technological advancements.

Fig. 1

Schematic overview of non-coding RNA types, microRNA biogenesis and their functions. a Two types of non-coding RNAs, short non-coding RNA and long non-coding RNA molecules, have been identified. The short non-coding RNA molecules can further be subdivided into microRNA (miRNA), small interfering RNA (siRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), piwi-interacting RNA (pi-RNA), transfer RNA (tRNA), ribosomal RNA (rRNA) and other uncharacterized small molecules. b Schematic overview of microRNA biogenesis and their function. In addition to the canonical pathway, involving the microprocessor complex, nuclear, and cytosolic processing, other sources such as introns, shRNAs, tRNAs and snoRNAs contribute to the miRNA biogenesis pathway. miRNAs exert their function predominantly by inhibiting translation in dividing cells, but they can also activate translation in quiescent cells

Fig. 2

Schematic diagram highlighting microRNAs that have been identified to show differential expression in various neurodegenerative diseases. The miRNAs shown have been identified using a variety of different techniques, as described throughout the text. Although several miRNAs are specific to a given class of neurodegenerative disease many also overlap suggesting their involvement in more common pathways, such as neuronal cell death. As both aging and autophagy are associated with neurodegeneration there are also shared miRNAs between these two processes and the four main neurodegenerative disease states