All's well that transcribes well: non-coding RNAs and post-stroke brain damage

Abstract

The mammalian genome is replete with various classes of non-coding (nc) RNA genes. Many of them actively transcribe, and their relevance to CNS diseases is just beginning to be understood. CNS is one of the organs in the body that shows very high ncRNAs activity. Recent studies demonstrated that cerebral ischemia rapidly changes the expression profiles of different classes of ncRNAs: including microRNA, long noncoding RNA and piwi-interacting RNA. Several studies further showed that post-ischemic neuronal death and/or plasticity/regeneration can be altered by modulating specific microRNAs. These studies are of interest for therapeutic development as they may contribute to identifying new ncRNA targets that can be modulated to prevent secondary brain damage after stroke.

Keywords: Cerebral ischemia; Molecular mechanisms; Pathophysiology; Transcription; Translation; microRNA.

Fig. 1. Bioinformatics correlation of the miRNAs and the inflammatory mRNAs altered after focal ischemia

Stroke-responsive miRNAs can modulate mRNAs that mediate the cerebral pro-inflammatory response including cytokines, chemokines, cell adhesion molecules and free radical generating enzymes. This figure appeared previously as supplemental information in Dharap et al. (2009).

Fig. 2. Bioinformatics correlation of the miRNAs and the neuroprotective mRNAs altered after focal ischemia

Many neuroprotective and neurorestorative mRNAs are also the predicted targets of the stroke-responsive miRNAs. These include protein chaperones, antioxidant enzymes and growth factors. This figure appeared previously as supplemental information in Dharap et al. (2009).

Fig. 3. Bioinformatics correlation of the miRNAs and the transcription factor mRNAs altered after focal ischemia

Transcription factor mRNAs are a major group of predicted targets of the miRNAs altered in the post-ischemic brain. Some of them are known promoters of inflammation and neuronal death, while some are upstream to neuroprotective pathways. This figure appeared previously as supplemental information in Dharap et al. (2009).

Fig. 4

Many pathophysiologic mechanisms synergistically contribute to neuronal death and neurologic dysfunction after stroke. Excitotoxicity, energy failure and ionic imbalance start within minutes after stroke and continue for days. Immediately after the insult, increased glutamate release combined with a failure of the glutamate transporters lead to elevated glutamate levels in the synaptic cleft, contributing to excitotoxic neuronal death. The energy failure leads to ionic imbalance that induces water to rush in leading to edema. Oxidative stress, ER stress and inflammation that start within hours after stroke are major events that lead to neuronal death if not controlled. A massive induction of HSPs in the post-ischemic brain might be an endogenous effort of self-protection. In addition, transcriptional and translational failure that encompasses altered expression of transcription factors, epigenetic changes like altered promoter methylation, post-translational modifications and altered ncRNA function also play a role in post-stroke pathophysiology.