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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

Schematic drawing of the nigrostrital circuitry in the normal brain (A) and the parkinsonian brain (B). Red, green and gray lines indicate dopaminergic neurons, GABAergic neurons and glutamatergic neurons, respectively. The thin lines indicate normal signal transmission, whereas thick lines and dashed lines indicate enhanced and attenuated signal transmission, respectively. Dopamine depletion in the Putamen (caused by death of the dopaminergic neurons of Substantia nigra) leads to decreased stimulation of the Substance P positive (SP) GABAergic neurons (the direct pathway) that usually receive input from the Substantia nigra through the stimulatory D1-receptor [143,144,145,151]. This leads to decreased inhibition of the GABAergic projection neurons of the Globus Palidus interna (GPi). Therefore, the glutamatergic neurons of the Thalamus are inhibited more strongly, leading to decreased stimulation of neurons in the motor cortex [143,144,145,151]. This results in the hypokinetic symptoms characteristic for PD. The decreased dopaminergic input to the Enkephalin positive (EP) GABAergic neurons (the indirect pathway) that usually receive input from the Substantia nigra through the inhibitory D2-receptors leads to increased activity of these neurons, which in turn reduces the inhibiting stimulus to the glutamatergic neurons of the Subthalamic nucleus (STN) [143,144,145,151]. Again this leads to increased inhibitory input to the thalamic neurons, which exacerbate the hypokinesia.
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genes-04-00457-f002: Schematic drawing of the nigrostrital circuitry in the normal brain (A) and the parkinsonian brain (B). Red, green and gray lines indicate dopaminergic neurons, GABAergic neurons and glutamatergic neurons, respectively. The thin lines indicate normal signal transmission, whereas thick lines and dashed lines indicate enhanced and attenuated signal transmission, respectively. Dopamine depletion in the Putamen (caused by death of the dopaminergic neurons of Substantia nigra) leads to decreased stimulation of the Substance P positive (SP) GABAergic neurons (the direct pathway) that usually receive input from the Substantia nigra through the stimulatory D1-receptor [143,144,145,151]. This leads to decreased inhibition of the GABAergic projection neurons of the Globus Palidus interna (GPi). Therefore, the glutamatergic neurons of the Thalamus are inhibited more strongly, leading to decreased stimulation of neurons in the motor cortex [143,144,145,151]. This results in the hypokinetic symptoms characteristic for PD. The decreased dopaminergic input to the Enkephalin positive (EP) GABAergic neurons (the indirect pathway) that usually receive input from the Substantia nigra through the inhibitory D2-receptors leads to increased activity of these neurons, which in turn reduces the inhibiting stimulus to the glutamatergic neurons of the Subthalamic nucleus (STN) [143,144,145,151]. Again this leads to increased inhibitory input to the thalamic neurons, which exacerbate the hypokinesia.

Mentions: In PD the selective degeneration of dopaminergic neurons of substantia nigra results in several changes of the neural circuitry controlling motor function. The dopaminergic neurons innervate two different GABAeregic neuronal populations in the Putamen through D1 and D2 receptors, respectively. Since the D1 receptor is stimulatory whereas the D2 receptor is inhibitory, the decreased dopaminergic innervation results in decreased activity of one population (the Substance P positive neurons) and increased activity of the other (the Enkephalin positive neurons). Through a complex neural circuitry, both of these events lead to the reduction of the glutamatergic Thalamic innervations of neurons in the motor cortex resulting in the hypokinetic features that characterize PD (Figure 2) [143,144]. Furthermore, the enkephalin positive GABAergic neurons in the Putamen show up-regulated GABA production due to transcriptional induction of the GABA producing enzyme GAD67 [145], which exacerbate the disturbed neuronal transmission of this pathway [146,147]. This elevated GABA production has furthermore been correlated to motor symptoms [143]. Reversing the pathological increase in GAD67 might then be beneficial to the symptoms of PD. This has been shown by Hovarth and colleagues, who showed that injection of a lentiviral vector expressing shRNAs or artificial miRNA targeted against GAD67 restores normal GABA levels in the Striatum, and that this normalized GABA level is accompanied by the reversal of the pathological increase in neuronal activity that comes with nigrostriatal denervation [111,148]. However, knocking down the GABA producing enzyme in both the Substance P and Enkephalin positive neuronal populations may result in decreased efficacy of treatment or even in side effects, since the reduced GABAergic activity of the Substance P positive population caused by the nigrostriatal denervation will be exacerbated by knock down of the GABA producing enzymes in this particular neuronal population. Hence, specific expression of shRNAs or artificial miRNAs in the Enkephalin positive population might convey a targeted and more precise manipulation of the nigrostriatal system in PD. Such cell specific knock-down in the brain has been achieved [40] and the Enkephalin promoter has been shown to be up regulated upon nigrostriatal dopamine depletion [149,150], suggesting that knock down of GAD67 driven by the Enkephalin promoter might be a feasible therapeutic strategy in PD.


Antisense gene silencing: therapy for neurodegenerative disorders?

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

Schematic drawing of the nigrostrital circuitry in the normal brain (A) and the parkinsonian brain (B). Red, green and gray lines indicate dopaminergic neurons, GABAergic neurons and glutamatergic neurons, respectively. The thin lines indicate normal signal transmission, whereas thick lines and dashed lines indicate enhanced and attenuated signal transmission, respectively. Dopamine depletion in the Putamen (caused by death of the dopaminergic neurons of Substantia nigra) leads to decreased stimulation of the Substance P positive (SP) GABAergic neurons (the direct pathway) that usually receive input from the Substantia nigra through the stimulatory D1-receptor [143,144,145,151]. This leads to decreased inhibition of the GABAergic projection neurons of the Globus Palidus interna (GPi). Therefore, the glutamatergic neurons of the Thalamus are inhibited more strongly, leading to decreased stimulation of neurons in the motor cortex [143,144,145,151]. This results in the hypokinetic symptoms characteristic for PD. The decreased dopaminergic input to the Enkephalin positive (EP) GABAergic neurons (the indirect pathway) that usually receive input from the Substantia nigra through the inhibitory D2-receptors leads to increased activity of these neurons, which in turn reduces the inhibiting stimulus to the glutamatergic neurons of the Subthalamic nucleus (STN) [143,144,145,151]. Again this leads to increased inhibitory input to the thalamic neurons, which exacerbate the hypokinesia.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

genes-04-00457-f002: Schematic drawing of the nigrostrital circuitry in the normal brain (A) and the parkinsonian brain (B). Red, green and gray lines indicate dopaminergic neurons, GABAergic neurons and glutamatergic neurons, respectively. The thin lines indicate normal signal transmission, whereas thick lines and dashed lines indicate enhanced and attenuated signal transmission, respectively. Dopamine depletion in the Putamen (caused by death of the dopaminergic neurons of Substantia nigra) leads to decreased stimulation of the Substance P positive (SP) GABAergic neurons (the direct pathway) that usually receive input from the Substantia nigra through the stimulatory D1-receptor [143,144,145,151]. This leads to decreased inhibition of the GABAergic projection neurons of the Globus Palidus interna (GPi). Therefore, the glutamatergic neurons of the Thalamus are inhibited more strongly, leading to decreased stimulation of neurons in the motor cortex [143,144,145,151]. This results in the hypokinetic symptoms characteristic for PD. The decreased dopaminergic input to the Enkephalin positive (EP) GABAergic neurons (the indirect pathway) that usually receive input from the Substantia nigra through the inhibitory D2-receptors leads to increased activity of these neurons, which in turn reduces the inhibiting stimulus to the glutamatergic neurons of the Subthalamic nucleus (STN) [143,144,145,151]. Again this leads to increased inhibitory input to the thalamic neurons, which exacerbate the hypokinesia.
Mentions: In PD the selective degeneration of dopaminergic neurons of substantia nigra results in several changes of the neural circuitry controlling motor function. The dopaminergic neurons innervate two different GABAeregic neuronal populations in the Putamen through D1 and D2 receptors, respectively. Since the D1 receptor is stimulatory whereas the D2 receptor is inhibitory, the decreased dopaminergic innervation results in decreased activity of one population (the Substance P positive neurons) and increased activity of the other (the Enkephalin positive neurons). Through a complex neural circuitry, both of these events lead to the reduction of the glutamatergic Thalamic innervations of neurons in the motor cortex resulting in the hypokinetic features that characterize PD (Figure 2) [143,144]. Furthermore, the enkephalin positive GABAergic neurons in the Putamen show up-regulated GABA production due to transcriptional induction of the GABA producing enzyme GAD67 [145], which exacerbate the disturbed neuronal transmission of this pathway [146,147]. This elevated GABA production has furthermore been correlated to motor symptoms [143]. Reversing the pathological increase in GAD67 might then be beneficial to the symptoms of PD. This has been shown by Hovarth and colleagues, who showed that injection of a lentiviral vector expressing shRNAs or artificial miRNA targeted against GAD67 restores normal GABA levels in the Striatum, and that this normalized GABA level is accompanied by the reversal of the pathological increase in neuronal activity that comes with nigrostriatal denervation [111,148]. However, knocking down the GABA producing enzyme in both the Substance P and Enkephalin positive neuronal populations may result in decreased efficacy of treatment or even in side effects, since the reduced GABAergic activity of the Substance P positive population caused by the nigrostriatal denervation will be exacerbated by knock down of the GABA producing enzymes in this particular neuronal population. Hence, specific expression of shRNAs or artificial miRNAs in the Enkephalin positive population might convey a targeted and more precise manipulation of the nigrostriatal system in PD. Such cell specific knock-down in the brain has been achieved [40] and the Enkephalin promoter has been shown to be up regulated upon nigrostriatal dopamine depletion [149,150], suggesting that knock down of GAD67 driven by the Enkephalin promoter might be a feasible therapeutic strategy in PD.

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