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Research Article
Maurizio Romano
Department of Life Sciences, University of Trieste, Via A. Valerio 28, 34127 - Trieste Italy
Corresponding Author
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The expression of TDP-43, the main component of neuronal intracellular inclusions across a broad spectrum of ALS and FTD disorders, is developmentally regulated and studies in vivo have shown that TDP-43 overexpression can be toxic, even before observation of pathological aggregates. Starting from these observations, the regulation of its expression at transcriptional level might represent a further key element for the pathogenesis of neurodegenerative diseases. Therefore, we have characterized the human TARDBP promoter, in order to study the transcriptional mechanisms of expression. Mapping of cis-acting elements by luciferase assays in different cells outlined that the activity of the promoter seems to be higher in cell lines of neuronal origin. We have identified the first 400 nucleotides upstream from the transcription start site as the minimal region with a significant transcription activity. In addition, we tested the effects of two SNPs found in the the promoter region of ALS patients and observed no significant effect on transcription levels. Then, TDP-43 overexpression did not affect significantly the activity of its promoter, suggesting that TDP-43 does not influence its own transcription. Finally, the presence of the 5'UTR sequence and of intron-1 splicing seem to impact positively on TDP-43 expression at transcriptional level.
Keywords
TARDBP, TDP-43, promoter, 5'UTR, splicing, luciferase
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CURRENT STATUS: Under Review
Version 1
Posted 25 Nov, 2020
No community comments so far
Editorial decision: Major revision
On 22 Dec, 2020
Reviews received
Received 26 Nov, 2020
Reviewers agreed
On 24 Nov, 2020
Reviewers invited
Invitations sent on 23 Nov, 2020
Editor assigned
On 23 Nov, 2020
Editor invited
On 23 Nov, 2020
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On 23 Nov, 2020
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On 17 Nov, 2020
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Subject Areas
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This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Maurizio Romano
Department of Life Sciences, University of Trieste, Via A. Valerio 28, 34127 - Trieste Italy
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 25 Nov, 2020
No community comments so far
Editorial decision: Major revision
On 22 Dec, 2020
Reviews received
Received 26 Nov, 2020
Reviewers agreed
On 24 Nov, 2020
Reviewers invited
Invitations sent on 23 Nov, 2020
Editor assigned
On 23 Nov, 2020
Editor invited
On 23 Nov, 2020
Submission checks complete
On 23 Nov, 2020
First submitted
On 17 Nov, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Biotechnology and Bioengineering
License:
This work is licensed under a CC BY 4.0 License. Read Full License
The expression of TDP-43, the main component of neuronal intracellular inclusions across a broad spectrum of ALS and FTD disorders, is developmentally regulated and studies in vivo have shown that TDP-43 overexpression can be toxic, even before observation of pathological aggregates. Starting from these observations, the regulation of its expression at transcriptional level might represent a further key element for the pathogenesis of neurodegenerative diseases. Therefore, we have characterized the human TARDBP promoter, in order to study the transcriptional mechanisms of expression. Mapping of cis-acting elements by luciferase assays in different cells outlined that the activity of the promoter seems to be higher in cell lines of neuronal origin. We have identified the first 400 nucleotides upstream from the transcription start site as the minimal region with a significant transcription activity. In addition, we tested the effects of two SNPs found in the the promoter region of ALS patients and observed no significant effect on transcription levels. Then, TDP-43 overexpression did not affect significantly the activity of its promoter, suggesting that TDP-43 does not influence its own transcription. Finally, the presence of the 5'UTR sequence and of intron-1 splicing seem to impact positively on TDP-43 expression at transcriptional level.
Figure 1
Figure 1
Figure 2
Figure 2
Figure 3
Figure 3
Figure 4
Figure 4
Figure 5
Figure 5
Figure 6
Figure 6
Figure 7
Figure 7
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