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Antisense gene silencing: therapy for neurodegenerative disorders?

Nielsen TT, Nielsen JE - Genes (Basel) (2013)

Bottom Line: Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function.With the subsequent discovery that RNAi could also be applied to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique.This review will focus on how RNAi has developed over the years and how the technique is exploited in a pre-clinical and clinical perspective in relation to neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Section 6702, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. troelsn@sund.ku.dk.

ABSTRACT
Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique. This review will focus on how RNAi has developed over the years and how the technique is exploited in a pre-clinical and clinical perspective in relation to neurodegenerative disorders.

No MeSH data available.


Related in: MedlinePlus

Pathways of RNAi.
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genes-04-00457-f001: Pathways of RNAi.

Mentions: The discovery of short RNA duplexes as the mediators of the sequence specific gene silencing led to the elucidation of a general mechanism by which RNAi imposes its effect, namely through a series of cellular events in response to dsRNAs. It was shown that long dsRNAs are cleaved by a cytoplasmic protein called Dicer to produce small interfering RNAs (siRNAs) typically consisting of two 21-nucleotide single stranded RNAs forming a 19 bp duplex with 2-nucleotide (nt) 3' overhangs [9,10,11]. The siRNAs are subsequently loaded into a protein complex termed the RNA induced silencing complex (RISC) in which one strand (the passenger strand) of the siRNA is displaced. The remaining strand (the guiding strand) guides RISC to target mRNA complementary to the guiding strand for endonucleolytic cleavage or translational repression (Figure 1A) [2,9]. The description of this novel pathway led to the discovery of a new group of non-coding RNA molecules, the microRNAs (miRNA). Although small RNA transcripts of approximately 22 and 61 bp complementary to the 3' untranslated region (UTR) of the lin-14 gene of C. elegans were identified in the early 1990s [12], it was not until the early 2000s that such transcripts were recognized as part of an individual group of RNAs with important biological functions—the miRNAs. It became evident that miRNAs are important post-transcriptional regulators of gene expression and that their functions are highly conserved in plants and animals [13]. Today, more than 1,000 miRNAs have been identified in humans [14]. They are transcribed from both introns and exons by polymerase II promoters (transcripts are termed pri-miRNA) and are expressed in a highly regulated temporo-spatial manner. The pri-miRNAs are processed in the nucleus by the endonuclease Drosha to form shorter stem-loop-structures of approximately 70 bp in length (pre-miRNAs) [15,16]. The pre-miRNAs are exported from the nucleus and processed by another endonuclease, Dicer, to form the mature miRNA that consists of 22 nt RNA molecules forming 20 nt RNA duplexes with 2 nt 3' overhangs [16,17,18]. As in the case of the siRNAs the mature miRNAs are loaded into RISC thereby targeting specific mRNAs [19], and siRNAs or dsRNAs thus enter the endogenous RNA processing machinery and share the cellular mechanisms of action with miRNAs.


Antisense gene silencing: therapy for neurodegenerative disorders?

Nielsen TT, Nielsen JE - Genes (Basel) (2013)

Pathways of RNAi.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3924827&req=5

genes-04-00457-f001: Pathways of RNAi.
Mentions: The discovery of short RNA duplexes as the mediators of the sequence specific gene silencing led to the elucidation of a general mechanism by which RNAi imposes its effect, namely through a series of cellular events in response to dsRNAs. It was shown that long dsRNAs are cleaved by a cytoplasmic protein called Dicer to produce small interfering RNAs (siRNAs) typically consisting of two 21-nucleotide single stranded RNAs forming a 19 bp duplex with 2-nucleotide (nt) 3' overhangs [9,10,11]. The siRNAs are subsequently loaded into a protein complex termed the RNA induced silencing complex (RISC) in which one strand (the passenger strand) of the siRNA is displaced. The remaining strand (the guiding strand) guides RISC to target mRNA complementary to the guiding strand for endonucleolytic cleavage or translational repression (Figure 1A) [2,9]. The description of this novel pathway led to the discovery of a new group of non-coding RNA molecules, the microRNAs (miRNA). Although small RNA transcripts of approximately 22 and 61 bp complementary to the 3' untranslated region (UTR) of the lin-14 gene of C. elegans were identified in the early 1990s [12], it was not until the early 2000s that such transcripts were recognized as part of an individual group of RNAs with important biological functions—the miRNAs. It became evident that miRNAs are important post-transcriptional regulators of gene expression and that their functions are highly conserved in plants and animals [13]. Today, more than 1,000 miRNAs have been identified in humans [14]. They are transcribed from both introns and exons by polymerase II promoters (transcripts are termed pri-miRNA) and are expressed in a highly regulated temporo-spatial manner. The pri-miRNAs are processed in the nucleus by the endonuclease Drosha to form shorter stem-loop-structures of approximately 70 bp in length (pre-miRNAs) [15,16]. The pre-miRNAs are exported from the nucleus and processed by another endonuclease, Dicer, to form the mature miRNA that consists of 22 nt RNA molecules forming 20 nt RNA duplexes with 2 nt 3' overhangs [16,17,18]. As in the case of the siRNAs the mature miRNAs are loaded into RISC thereby targeting specific mRNAs [19], and siRNAs or dsRNAs thus enter the endogenous RNA processing machinery and share the cellular mechanisms of action with miRNAs.

Bottom Line: Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function.With the subsequent discovery that RNAi could also be applied to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique.This review will focus on how RNAi has developed over the years and how the technique is exploited in a pre-clinical and clinical perspective in relation to neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Section 6702, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark. troelsn@sund.ku.dk.

ABSTRACT
Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique. This review will focus on how RNAi has developed over the years and how the technique is exploited in a pre-clinical and clinical perspective in relation to neurodegenerative disorders.

No MeSH data available.


Related in: MedlinePlus