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RNA polymerase III drives alternative splicing of the potassium channel-interacting protein contributing to brain complexity and neurodegeneration.

Massone S, Vassallo I, Castelnuovo M, Fiorino G, Gatta E, Robello M, Borghi R, Tabaton M, Russo C, Dieci G, Cancedda R, Pagano A - J. Cell Biol. (2011)

Bottom Line: We found that IL1-α-dependent up-regulation of 38A, a small ribonucleic acid (RNA) polymerase III-transcribed RNA, drives the synthesis of an alternatively spliced form of the potassium channel-interacting protein (KCNIP4).Notably, synthesis of the variant KCNIP4 isoform is also detrimental to brain physiology, as it results in the concomitant blockade of the fast kinetics of potassium channels.This alternative splicing shift is observed at high frequency in tissue samples from Alzheimer's disease patients, suggesting that RNA polymerase III cogenes may be upstream determinants of alternative splicing that significantly contribute to homeostasis and pathogenesis in the brain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, Biology, and Genetics, National Institute for Cancer Research, 16132 Genoa, Italy.

ABSTRACT
Alternative splicing generates protein isoforms that are conditionally or differentially expressed in specific tissues. The discovery of factors that control alternative splicing might clarify the molecular basis of biological and pathological processes. We found that IL1-α-dependent up-regulation of 38A, a small ribonucleic acid (RNA) polymerase III-transcribed RNA, drives the synthesis of an alternatively spliced form of the potassium channel-interacting protein (KCNIP4). The alternative KCNIP4 isoform cannot interact with the γ-secretase complex, resulting in modification of γ-secretase activity, amyloid precursor protein processing, and increased secretion of β-amyloid enriched in the more toxic Aβ x-42 species. Notably, synthesis of the variant KCNIP4 isoform is also detrimental to brain physiology, as it results in the concomitant blockade of the fast kinetics of potassium channels. This alternative splicing shift is observed at high frequency in tissue samples from Alzheimer's disease patients, suggesting that RNA polymerase III cogenes may be upstream determinants of alternative splicing that significantly contribute to homeostasis and pathogenesis in the brain.

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A schematic model of the possible contribution of the 38A cogene to neurodegeneration.
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fig10: A schematic model of the possible contribution of the 38A cogene to neurodegeneration.

Mentions: In light of the aforementioned findings, we propose a model that is in line with the amyloid hypothesis and proposes a series of inflammation-dependent early events that ultimately lead to altered amyloid production and to the impairment of a voltage-dependent current contributing to the excitatory properties to neurons (Fig. 10). Although at present it is not clear whether 38A is essential for AD onset or is rather part of a pathological condition of the brain that occurs in numerous neurodegenerative disorders, this model provides a novel way to investigate neurodegenerations and brain function based on an alternative cascade of reactions unexpectedly controlled by a PolIII-transcribed ncRNA. Indeed, although the genetic analysis of 38A alleles in AD and controls does not support its role in the disease as a single determinant element, the unbalanced frequency of its promoter configurations suggests its contribution to the disease in association with other elements. Moreover, the cell type–specific regulation of 38A suggests the involvement of still elusive PolIII-specific transcription factors whose identification might reveal new genes associated with sporadic AD. In this context, a detailed investigation of the transcriptional properties of 38A promoter variants might allow us to identify possible AD risk factors and/or druglike compounds able to decrease the amyloid production via 38A transcription inhibition. In conclusion, this work provides novel information of particular relevance, as (a) it proposes a novel mechanism by which the alternative splicing can be involved in brain pathologies, (b) it proposes a role for PolIII-transcribed ncRNAs in orchestrating the regulation of a mosaic of alternative protein forms in different tissues or cell conditions, and (c) it indicates new specific genomic loci to which genetic variations that account for pathological manifestations might be mapped.


RNA polymerase III drives alternative splicing of the potassium channel-interacting protein contributing to brain complexity and neurodegeneration.

Massone S, Vassallo I, Castelnuovo M, Fiorino G, Gatta E, Robello M, Borghi R, Tabaton M, Russo C, Dieci G, Cancedda R, Pagano A - J. Cell Biol. (2011)

A schematic model of the possible contribution of the 38A cogene to neurodegeneration.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3105541&req=5

fig10: A schematic model of the possible contribution of the 38A cogene to neurodegeneration.
Mentions: In light of the aforementioned findings, we propose a model that is in line with the amyloid hypothesis and proposes a series of inflammation-dependent early events that ultimately lead to altered amyloid production and to the impairment of a voltage-dependent current contributing to the excitatory properties to neurons (Fig. 10). Although at present it is not clear whether 38A is essential for AD onset or is rather part of a pathological condition of the brain that occurs in numerous neurodegenerative disorders, this model provides a novel way to investigate neurodegenerations and brain function based on an alternative cascade of reactions unexpectedly controlled by a PolIII-transcribed ncRNA. Indeed, although the genetic analysis of 38A alleles in AD and controls does not support its role in the disease as a single determinant element, the unbalanced frequency of its promoter configurations suggests its contribution to the disease in association with other elements. Moreover, the cell type–specific regulation of 38A suggests the involvement of still elusive PolIII-specific transcription factors whose identification might reveal new genes associated with sporadic AD. In this context, a detailed investigation of the transcriptional properties of 38A promoter variants might allow us to identify possible AD risk factors and/or druglike compounds able to decrease the amyloid production via 38A transcription inhibition. In conclusion, this work provides novel information of particular relevance, as (a) it proposes a novel mechanism by which the alternative splicing can be involved in brain pathologies, (b) it proposes a role for PolIII-transcribed ncRNAs in orchestrating the regulation of a mosaic of alternative protein forms in different tissues or cell conditions, and (c) it indicates new specific genomic loci to which genetic variations that account for pathological manifestations might be mapped.

Bottom Line: We found that IL1-α-dependent up-regulation of 38A, a small ribonucleic acid (RNA) polymerase III-transcribed RNA, drives the synthesis of an alternatively spliced form of the potassium channel-interacting protein (KCNIP4).Notably, synthesis of the variant KCNIP4 isoform is also detrimental to brain physiology, as it results in the concomitant blockade of the fast kinetics of potassium channels.This alternative splicing shift is observed at high frequency in tissue samples from Alzheimer's disease patients, suggesting that RNA polymerase III cogenes may be upstream determinants of alternative splicing that significantly contribute to homeostasis and pathogenesis in the brain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, Biology, and Genetics, National Institute for Cancer Research, 16132 Genoa, Italy.

ABSTRACT
Alternative splicing generates protein isoforms that are conditionally or differentially expressed in specific tissues. The discovery of factors that control alternative splicing might clarify the molecular basis of biological and pathological processes. We found that IL1-α-dependent up-regulation of 38A, a small ribonucleic acid (RNA) polymerase III-transcribed RNA, drives the synthesis of an alternatively spliced form of the potassium channel-interacting protein (KCNIP4). The alternative KCNIP4 isoform cannot interact with the γ-secretase complex, resulting in modification of γ-secretase activity, amyloid precursor protein processing, and increased secretion of β-amyloid enriched in the more toxic Aβ x-42 species. Notably, synthesis of the variant KCNIP4 isoform is also detrimental to brain physiology, as it results in the concomitant blockade of the fast kinetics of potassium channels. This alternative splicing shift is observed at high frequency in tissue samples from Alzheimer's disease patients, suggesting that RNA polymerase III cogenes may be upstream determinants of alternative splicing that significantly contribute to homeostasis and pathogenesis in the brain.

Show MeSH
Related in: MedlinePlus