Non-coding RNA networks underlying cognitive disorders across the lifespan

Abstract

Non-coding RNAs (ncRNAs) and their associated regulatory networks are increasingly being implicated in mediating a complex repertoire of neurobiological functions. Cognitive and behavioral processes are proving to be no exception. In this review, we discuss the emergence of many novel, diverse and rapidly expanding classes and subclasses of short and long ncRNAs. We briefly review the life cycles and molecular functions of these ncRNAs. We also examine how ncRNA circuitry mediates brain development, plasticity, stress responses and aging, and highlight its potential roles in the pathophysiology of cognitive disorders, including neural developmental and age-associated neurodegenerative diseases, as well as those that manifest throughout the lifespan.

Figure 1

Neurobiology of non-coding RNAs (ncRNAs). Depiction of interrelationships between ncRNA life cycle, ncRNA molecular functions, and ncRNA-mediated CNS processes underlying cognition (italics indicates putative roles). Diverse ncRNA subclasses are subject to distinct biogenesis and maturation pathways, fold into functional secondary and tertiary structures, are diversified via post-transcriptional processing, assemble into distinct ribonucleoprotein (RNP) complexes, and are transported intracellularly and intercellularly through various mechanisms. The molecular functions of these ncRNAs include roles in epigenetic, transcriptional, and post-transcriptional regulation; nuclear subdomain formation; translational control; and modulation of genomic integrity and plasticity. These ncRNAs mediate CNS processes underlying cognition including neural development, adult homeostasis and stress responses, and brain aging and might have roles in trans-neuronal signaling, bidirectional CNS-systemic communication, and multigenerational inheritance of cognitive and behavioral traits.

Figure 2

Production of RNAs. Schematic illustrating how diverse RNA species, including protein-coding messenger RNAs (mRNAs) and various classes of short and long non-coding RNAs (ncRNAs), may be derived from specific genomic loci and from other ncRNAs. Classes of short ncRNAs with characterized molecular functions (illustrated in red) include transfer RNAs (tRNAs), microRNAs (miRNAs), endogenous short interfering RNAs (endo-siRNAs), PIWI-interacting RNAs (piRNAs), and small nucleolar RNAs (snoRNAs). Novel classes of short ncRNAs with poorly characterized molecular functions (illustrated in gray) include (i) those associated with protein-coding gene boundaries (e.g., promoter-associated small RNAs [PASRs], termini-associated short RNAs [TASRs], antisense termini-associated short RNAs [aTASRs], transcription initiation RNAs [tiRNAs], splice-site RNAs [spliRNAs], and enhancer RNAs [eRNAs]) and (ii) others derived from the processing of small ncRNAs (e.g., small RNAs derived from small nucleolar RNAs [sdRNAs], microRNA-offset RNAs [moRNAs], and stress-induced tRNA-derived RNAs [sitRNAs]). Classes of long ncRNAs (lncRNAs; > 200 nucleotides) include those derived from intergenic regions and others organized in bidirectional, antisense, and overlapping configurations relative to protein-coding genes (illustrated in orange).