MicroRNAs as biomarkers for CNS disease

Abstract

For many neurological diseases, the efficacy and outcome of treatment depend on early detection. Diagnosis is currently based on the detection of symptoms and neuroimaging abnormalities, which appear at relatively late stages in the pathogenesis. However, the underlying molecular responses to genetic and environmental insults begin much earlier and non-coding RNA networks are critically involved in these cellular regulatory mechanisms. Profiling RNA expression patterns could thus facilitate presymptomatic disease detection. Obtaining indirect readouts of pathological processes is particularly important for brain disorders because of the lack of direct access to tissue for molecular analyses. Living neurons and other CNS cells secrete microRNA and other small non-coding RNA into the extracellular space packaged in exosomes, microvesicles, or lipoprotein complexes. This discovery, together with the rapidly evolving massive sequencing technologies that allow detection of virtually all RNA species from small amounts of biological material, has allowed significant progress in the use of extracellular RNA as a biomarker for CNS malignancies, neurological, and psychiatric diseases. There is also recent evidence that the interactions between external stimuli and brain pathological processes may be reflected in peripheral tissues, facilitating their use as potential diagnostic markers. In this review, we explore the possibilities and challenges of using microRNA and other small RNAs as a signature for neurodegenerative and other neuropsychatric conditions.

Keywords: CSF; biomarker; exosome; microRNA; next-generation sequencing; plasma.

Figure 1

A model for miRNA-based biomarker development: Disease-causing factors impact the brain both directly and indirectly (via immune and other cells), eliciting changes in gene and microRNA expression patterns. Many of these stimuli concurrently exert their influence on non-neuronal cells, where they also elicit a response. In CNS diseases, in the absence of direct access to diseased tissue, microRNA expression patterns from peripheral cells such as blood cells could be used a proxy for genome-environment interaction in the CNS. Moreover, microRNAs circulate stably in cerebrospinal fluid and plasma in extracellular vesicles and in lipoprotein complexes, and can be isolated from these body fluids and profiled. Information derived from peripheral sources could thus be used to construct a picture of neuronal function both in the healthy and the diseased state.