Non-coding RNAs in CNS disorders--the long and short of it.

By definition, non-coding RNAs (ncRNAs) are not translated into proteins. In mammals, >98% of the RNAs transcribed are ncRNAs that belong to many functional classes. The ncRNAs can be small (<30 nucleotides; e.g. microRNAs) to gigantic (~10,000 nucleotides; e.g. long noncoding RNAs). The precise functional significance of various classes of ncRNAs is still being evaluated, but many of them are thought to regulate chromatin function, transcription and translation to maintain genome fitness and function. CNS is known to have a very high level of ncRNA expression that might be essential for maintaining the complex brain functions. Many recent studies show that chronic and acute insults to CNS alter the expression profiles of ncRNAs with functional impact on the disease outcome. Emerging evidence also indicate that modulation of ncRNAs can be therapeutically beneficial. The goal of this special issue is to present the state-of-the art information regarding the functional significance of various classes of ncRNAs in brain pathologies. We extend the discussion to understand the significance of epigenetic changes as they function in concert with ncRNAs in controlling the molecular events under pathological conditions. Yin et al. discuss the significance of microRNAs altered after stroke in modulating the endothelial function and BBB integrity. Ouyang et al. show that microRNAs control apoptotic genes and thus neuronal death after cerebral ischemia. Strickland et al. and Sakai and Suzuki discuss the significance of microRNAs in pain processing which is a major detrimental pathological event after spinal cord injury. Brower et al. show that microRNAs also modulate cancer stem cells and thus control the progression of glioblastoma growth. Pathological conditions like stroke affect male and female brain very differently. In this context, Murphy et al. show that microRNAs and histone deacetylases might play a combined role in defining the sex differences in brain. Bourossa and Ratan discuss the cooperative action of microRNAs with histone deacetylation and the ensuing epigenetic changes in the progression of various neurological diseases. CNS insults including stroke significantly influence the white matter. In this context, Kassis et al. show the significance of microRNAs in controlling oligodendrocytes after stroke. Furthermore, Svaren show how microRNAs collaborate with transcription factors and other epigenetic factors to control myelinating glia in CNS. Of various ncRNAs, long noncoding RNAs are unique in their size and structure. Zhang and Leung discuss the functional significance of long noncoding RNAs in brain tumors and the clinical implications of controlling them. Despite the high rate of mutations in the genome, 481 regions (each longer than 200 base pairs) remained ultraconserved between humans and rodents. They transcribe RNAs that are thought to regulate chromatin structure and function. Mehta et al. show that rodent brain express many of these transcribed ultraconserved regions and might modulate the genes in their vicinity, which are important for normal brain function. PiRNAs are known to inhibit the transcription of RNAs coded by transposons and thus minimize mutations in the genome. Rajan et al. discuss the significance of piRNAs in CNS function. Overall, this special issue attempts to discuss many aspects of ncRNAs in CNS disorders including stroke, spinal cord injury, white matter integrity, brain tumors, sex differences and pain processing. These manuscripts highlight the contribution of various classes of ncRNAs including microRNAs, piRNAs, long noncoding RNAs and transcribed ultraconserved regions. I feel that the current understanding of the ncRNAs in brain function is exploding with potential to decipher their role in normal and injured CNS.