Frontiers in molecular neuroscience
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Compared to sites in protein-coding sequences many more targets undergoing adenosine to inosine (A-to-I) RNA editing were discovered in non-coding regions of human cerebral transcripts, particularly in genetic transposable elements called retrotransposons. We review here the interaction mechanisms of RNA editing and retrotransposons and their impact on normal function and human neurological diseases. Exemplarily, A-to-I editing of retrotransposons embedded in protein-coding mRNAs can contribute to protein abundance and function via circular RNA formation, alternative splicing, and exonization or silencing of retrotransposons. ⋯ We describe human diseases with involvement of the central nervous system including inborn errors of metabolism, neurodevelopmental disorders, neuroinflammatory and neurodegenerative and paroxysmal diseases, in which retrotransposons (Alu and/or L1 elements) appear to be causally involved in genetic rearrangements. Sole binding of single-stranded retrotransposon transcripts by RNA editing enzymes rather than enzymatic deamination may have a homeostatic effect on retrotransposon turnover. We also review evidence in support of the emerging pathophysiological function of A-to-I editing of retrotransposons in inflammation and its implication for different neurological diseases including amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's and Parkinson's disease, and epilepsy.
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Spinal cord injury (SCI) is mostly caused by trauma. As primary mechanical injury is unavoidable in SCI, a focus on the pathophysiology and underlying molecular mechanisms of SCI-induced secondary injury is necessary to develop promising treatments for SCI patients. Circular RNAs (circRNAs) are associated with various diseases. ⋯ The next section of the study was concerned with the prediction of circRNA/miRNA/mRNA interactions using bioinformatics analysis. In the final part of the study, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses indicated carbohydrate metabolic process was one of the most significant enrichments and meaningful terms after GO analysis, and the top two signaling pathways affected by the circRNAs-miRNAs axes were the AMP-activated protein kinase signaling pathway and the peroxisome related pathway. In summary, this study showed an altered circRNA expression pattern that may be involved in physiological and pathological processes in rats after traumatic SCI, providing deep insights into numerous possibilities for SCI treatment targets by regulating circRNAs.
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Injury of peripheral nerves can trigger neuropathic pain, producing allodynia and hyperalgesia via peripheral and central sensitization. Recent studies have focused on the role of the insular cortex (IC) in neuropathic pain. Because the IC is thought to store pain-related memories, translational regulation in this structure may reveal novel targets for controlling chronic pain. ⋯ Optical recording was conducted to observe the neural responses of the IC to peripheral stimulation. Rapamycin reduced mechanical allodynia and downregulated the expression of postsynaptic density protein 95 (PSD95), decreased neural excitability in the IC, thereby inhibiting neuropathic pain-induced synaptic plasticity. These findings suggest that mTOR signaling in the IC may be a critical molecular mechanism modulating neuropathic pain.
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Chemotherapy-induced peripheral neuropathy (CIPN), a debilitating major side effect of cancer treatment, is characterized by pain and sensory loss in hand and feet. Platinum-based chemotherapeutics like cisplatin frequently induce CIPN. The molecular mechanism underlying these neurotoxic symptoms is incompletely understood and there are no preventive or curative interventions. ⋯ Functionally, inhibition of mitochondrial p53 accumulation prevented the hallmarks of CIPN including mechanical allodynia, peripheral sensory loss (numbness) as quantified by an adhesive-removal task, and loss of intra-epidermal nerve fibers. In conclusion, PFT-μ is a potential neuroprotective agent that prevents cisplatin-induced mitochondrial dysfunction in DRG and peripheral nerves thereby protecting against CIPN through blockade of the early cisplatin-induced increase in mitochondrial p53. Notably, there is accumulating evidence that PFT-μ has anti-tumor activities and could therefore be an attractive candidate to prevent CIPN while promoting tumor cell death.
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Although studies provide insights into the neurobiology of stress and depression, the exact molecular mechanisms underlying their pathologies remain largely unknown. Long non-coding RNA (lncRNA) has been implicated in brain functions and behavior. A potential link between lncRNA and psychiatric disorders has been proposed. ⋯ Importantly, 57% of the identified regulatory lncRNAs significantly correlated with 18 different synapse-related functions. Thus, the current study identifies for the first time distinct groups of lncRNAs regulated by induction of learned helplessness in the mouse brain. Our results suggest that lncRNA-directed regulatory mechanisms might contribute to stress-induced pathologies; in particular, to inescapable stress-induced synaptic modifications.