MicroRNAs (miRNAs) in neurodegenerative diseases

Abstract

Aging-related neurodegenerative diseases (NDs) are the culmination of many different genetic and environmental influences. Prior studies have shown that RNAs are pathologically altered during the inexorable course of some NDs. Recent evidence suggests that microRNAs (miRNAs) may be a contributing factor in neurodegeneration. miRNAs are brain-enriched, small ( approximately 22 nucleotides) non-coding RNAs that participate in mRNA translational regulation. Although discovered in the framework of worm development, miRNAs are now appreciated to play a dynamic role in many mammalian brain-related biochemical pathways, including neuroplasticity and stress responses. Research about miRNAs in the context of neurodegeneration is accumulating rapidly, and the goal of this review is to provide perspective for these new data that may be helpful to specialists in either field. An overview is provided about the normal functions for miRNAs, including some of the newer concepts related to the human brain. Recently published studies pertaining to the roles of miRNAs in NDs--including Alzheimer's disease, Parkinson's disease and triplet repeat disorders-are described. Finally, a discussion is included with theoretical syntheses and possible future directions in exploring the nexus between miRNA and ND research.

Figure 1

In the mammalian brain as elsewhere, miRNAs subserve multiple fundamental biological roles. Many miRNAs are thought to interact with thousands of different targets. Post‐transcriptional RNA editing may change mRNA target specifity. References for the different hypothesized functions of miRNAs are given in the text.

Figure 2

In situ hybridization (ISH) from normal human brains for miRNAs gives an idea of how miRNAs are expressed in neuroanatomical areas that are vulnerable to NDs. A–C show hippocampus. A,B shows miRNAs (miR‐124 and miR‐320) that are expressed predominantly in neurons. By contrast, let‐7b is expressed in both neurons and glia, so cells outside the neuronal layers (such as the molecular layer, pink star, of the dentate granules, dg) are stained. D shows that cells of the superficial layer of entorhinal cortex are also stained avidly using a miR‐124 probe. In the substantia nigra, miR‐320 labels the pigment‐containing cells (E), but miR‐107 only labels them barely if at all (F). Scale bars: A–D = 500 µM; E = 125 µM; F = 62.5 µM. ISH was performed according to the protocol previously described (89) except fixed brain was cut with a freezing microtome.

Figure 3

Not only does a given miRNA recognize many mRNA targets, but the 3′ untranslated region (3′UTR) of many mRNAs are also the potential targets for many different miRNAs. Here are two examples that are relevant to NDs, the beta‐amyloid precursor protein (APP) and alpha‐synuclein (SNCA). miRNA target predictions are from the miRBASE registry (http://microrna.sanger.ac.uk/targets/v4/), and have not been validated. APP is predicted to be recognized by the products of 41 different miRNA genes, and SNCA is predicted to be recognized by that of 12.

Figure 4

A schematic diagram about some roles miRNAs may play in NDs. The brains of persons at risk for NDs are subjected to chronic stimuli that can perturb specific and/or global miRNA expression. Either the aberrant stimulation or inhibition of miRNA expression may be associated with pathways involved in NDs or neuroprotection.