Transcriptional Silencing in Nervous System

Introduction of Transcriptional Silencing

In recent years, we have a deeper understanding of the functions of RNA. Different forms of RNA have also been found, including ribonucleic acid, RNA enzymes, ribozymes, and other RNA molecules. In this case, RNA-based transcriptional silencing has been developed against multiple human diseases, especially neurological diseases. Compared with other tissues, there are more unique gene sequences expressed in the brain and many genetic diseases present a neurological phenotype. What’s more, the complex blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier largely affect the effective treatment of neurological diseases. The development of transcriptional silencing might be a wonderful idea for neurological disease treatment in the clinic.

Transcriptional Silencing for Neurological Disease

In recent years, more and more studies have shown that transcriptional silencing presents great potentials in the mammalian nervous system. For example, RNAi-based gene silencing has been successfully demonstrated in mouse neuroblastoma cells, P19 cells, neural stem cells, and hippocampal neurons. In addition, the adenovirus vector shRNA expression also results in gene silencing in the mouse brain.

In this case, target identification and technology optimization would be the important challenges for transcriptional silencing against multiple diseases, including central nervous system (CNS) tumors, neurodegenerative disorders, and retinal disorders. In follow-up research, the unique cell biology of mammalian neurons should be better understood. Moreover, targeting siRNAs to specific cell populations is also essential due to the complexity of CNS.

Research Methods for Gene Silencing

In recent decades, there are a series of technologies developed for specific gene silencing, which including but not limited to:

• Antisense oligonucleotides - Using a steric blocking mechanism or the RNase H-dependent mechanism to affect gene expression. With poor efficacy and specificity in mammalian systems, especially compared with RNAi.
• Ribozymes - By cleaving mRNA molecules, gene expression can be inhibited. The enzymatic properties allow broad mRNA cleavage and specificity.
• RNA interference - A cellular defense mechanism against invaders induced by double-stranded RNA (dsRNA).
• Three prime untranslated regions and microRNAs - according to the special binding within the 3’-UTR, miRNAs would decrease the gene expression of their target mRNAs.

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