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Background:
TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile remains unknown.
Methods:
Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used a Ribotag approach combined with microarray and proteomic analyses to investigate the neuronal translational profiles in mouse model of ALS/FTD.
Results:
Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induces autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function.
Conclusions:
Our study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.
Keywords
Amyotrophic lateral sclerosis, fronto-temporal dementia, TDP-43, withaferin-A, autophagy, neurofilament, mRNA translation
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Peer Review Timeline
CURRENT STATUS: Published
View the published article at Molecular Neurodegeneration.
No community comments so far
Editorial decision: Accept
On 05 Dec, 2020
Review #2 received
Received 30 Nov, 2020
Reviewer #2 agreed
On 22 Nov, 2020
Review #1 received
Received 22 Nov, 2020
Reviewer #1 agreed
On 19 Nov, 2020
Editor assigned
On 18 Nov, 2020
Reviewers invited
Invitations sent on 18 Nov, 2020
Submission checks complete
On 18 Nov, 2020
Editor invited
On 18 Nov, 2020
Version 1
Posted 22 May, 2020
No comments provided
Editorial decision: Major revision
On 03 Sep, 2020
Review #2 received
Received 21 Aug, 2020
Review #1 received
Received 10 Jun, 2020
Reviewer #2 agreed
On 08 Jun, 2020
Reviewer #1 agreed
On 02 Jun, 2020
Reviewers invited
Invitations sent on 01 Jun, 2020
Editor assigned
On 18 May, 2020
Submission checks complete
On 17 May, 2020
Editor invited
On 17 May, 2020
First submitted
On 15 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
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A new preprint design is coming!
We have improved readability, clarity, accessibility, and opportunities for engagement.
See the published version of this preprint at Molecular Neurodegeneration.
This is a preprint, 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
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: Published
View the published article at Molecular Neurodegeneration.
No community comments so far
Editorial decision: Accept
On 05 Dec, 2020
Review #2 received
Received 30 Nov, 2020
Reviewer #2 agreed
On 22 Nov, 2020
Review #1 received
Received 22 Nov, 2020
Reviewer #1 agreed
On 19 Nov, 2020
Editor assigned
On 18 Nov, 2020
Reviewers invited
Invitations sent on 18 Nov, 2020
Submission checks complete
On 18 Nov, 2020
Editor invited
On 18 Nov, 2020
Version 1
Posted 22 May, 2020
No comments provided
Editorial decision: Major revision
On 03 Sep, 2020
Review #2 received
Received 21 Aug, 2020
Review #1 received
Received 10 Jun, 2020
Reviewer #2 agreed
On 08 Jun, 2020
Reviewer #1 agreed
On 02 Jun, 2020
Reviewers invited
Invitations sent on 01 Jun, 2020
Editor assigned
On 18 May, 2020
Submission checks complete
On 17 May, 2020
Editor invited
On 17 May, 2020
First submitted
On 15 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Molecular Neurodegeneration.
Background:
TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile remains unknown.
Methods:
Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used a Ribotag approach combined with microarray and proteomic analyses to investigate the neuronal translational profiles in mouse model of ALS/FTD.
Results:
Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induces autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function.
Conclusions:
Our study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
This is a list of supplementary files associated with this preprint. Click to download.
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