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Related Concept Videos

Alternative RNA Splicing02:18

Alternative RNA Splicing

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Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
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Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
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Pre-mRNA Processing: Modification of pre-mRNA Ends01:35

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In eukaryotic cells, transcripts made by RNA polymerase are modified and processed before exiting the nucleus. Unprocessed RNA is called precursor mRNA or pre-mRNA to distinguish it from mature mRNA.
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Riboswitches are non-coding mRNA domains that regulate the transcription and translation of downstream genes without the help of proteins. Riboswitches bind directly to a metabolite and can form unique stem-loop or hairpin structures in response to the amount of the metabolite present. They have two distinct regions – a metabolite-binding aptamer and an expression platform.
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Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
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A Reporter Based Cellular Assay for Monitoring Splicing Efficiency
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Small molecule splicing modifiers with systemic HTT-lowering activity.

Anuradha Bhattacharyya1, Christopher R Trotta1, Jana Narasimhan1

  • 1PTC Therapeutics, Inc. 100 Corporate Court, South Plainfield, NJ, USA.

Nature Communications
|December 16, 2021
PubMed
Summary
This summary is machine-generated.

New orally bioavailable small molecules effectively reduce huntingtin (HTT) protein levels throughout the central nervous system (CNS) and periphery. This novel approach targets pre-messenger RNA splicing to degrade HTT mRNA, offering a promising therapeutic strategy for Huntington's disease (HD).

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Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Huntington's disease (HD) is an inherited neurodegenerative disorder caused by expanded CAG trinucleotide repeats in the huntingtin (HTT) gene.
  • Mutant HTT protein's toxic gain-of-function drives HD pathogenesis, with animal models showing reduced HTT levels alleviate symptoms.
  • Current investigational drugs for HD require invasive delivery to the central nervous system (CNS) and lack broad CNS distribution.

Purpose of the Study:

  • To identify orally bioavailable small molecules for reducing huntingtin (HTT) protein levels.
  • To achieve broad distribution of therapeutic agents throughout the CNS.
  • To develop a novel therapeutic strategy for Huntington's disease (HD) by modulating HTT expression.

Main Methods:

  • Identification of orally bioavailable small molecules.
  • Assessment of CNS and peripheral distribution of these molecules.
  • Analysis of HTT expression levels following treatment.
  • Investigation of the mechanism involving selective modulation of pre-messenger RNA splicing, specifically promoting stop-codon pseudoexon inclusion.

Main Results:

  • Discovery of orally bioavailable small molecules demonstrating broad CNS distribution.
  • Consistent reduction of HTT expression in both the CNS and periphery.
  • Mechanism confirmed: compounds promote stop-codon pseudoexon inclusion, leading to HTT mRNA degradation.

Conclusions:

  • Orally bioavailable small molecules can effectively lower HTT expression throughout the CNS and periphery.
  • Targeting pre-messenger RNA splicing represents a novel and promising therapeutic approach for Huntington's disease (HD).
  • This strategy offers potential for improved treatment delivery and efficacy compared to existing investigational drugs.