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cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.

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Title: cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.
Authors: Ho, Diana M.1, Shaban, Muhammad2,3,4,5, Mahmood, Faisal2,3,4,5, Ganguly, Payel1, Todeschini, Leonardo1, Van Vactor, David1, Artavanis-Tsakonas, Spyros1 artavanis@hms.harvard.edu
Source: Proceedings of the National Academy of Sciences of the United States of America. 6/11/2024, Vol. 121 Issue 24, p1-9. 14p.
Subjects: Amyotrophic lateral sclerosis, Phospholipase D, Drosophila melanogaster, Motor neurons, Fruit flies
Abstract: Cytoplasmic mislocalization and aggregation of TDP-43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and are observed in the vast majority of both familial and sporadic cases. How these two interconnected processes are regulated on a molecular level, however, remains enigmatic. Genome-wide screens for modifiers of the ALS-associated genes TDP-43 and FUS have identified the phospholipase D (Pld) pathway as a key regulator of ALS-related phenotypes in the fruit fly Drosophila melanogaster [M. W. Kankel et al., Genetics 215, 747-766 (2020)]. Here, we report the results of our search for downstream targets of the enzymatic product of Pld, phosphatidic acid. We identify two conserved negative regulators of the cAMP/PKA signaling pathway, the phosphodiesterase dunce and the inhibitory subunit PKA-R2, as modifiers of pathogenic phenotypes resulting from overexpression of the Drosophila TDP-43 ortholog TBPH. We show that knockdown of either of these genes results in a mitigation of both TBPH aggregation and mislocalization in larval motor neuron cell bodies, as well as an amelioration of adult-onset motor defects and shortened lifespan induced by TBPH. We determine that PKA kinase activity is downstream of both TBPH and Pld and that overexpression of the PKA target CrebA can rescue TBPH mislocalization. These findings suggest a model whereby increasing cAMP/PKA signaling can ameliorate the molecular and functional effects of pathological TDP-43. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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DbLabel: Engineering Source
An: 177939367
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PubTypeId: academicJournal
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  Data: cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.
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  Data: <searchLink fieldCode="AR" term="%22Ho%2C+Diana+M%2E%22">Ho, Diana M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Shaban%2C+Muhammad%22">Shaban, Muhammad</searchLink><relatesTo>2,3,4,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Mahmood%2C+Faisal%22">Mahmood, Faisal</searchLink><relatesTo>2,3,4,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Ganguly%2C+Payel%22">Ganguly, Payel</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Todeschini%2C+Leonardo%22">Todeschini, Leonardo</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Van+Vactor%2C+David%22">Van Vactor, David</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Artavanis-Tsakonas%2C+Spyros%22">Artavanis-Tsakonas, Spyros</searchLink><relatesTo>1</relatesTo><i> artavanis@hms.harvard.edu</i>
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  Data: <searchLink fieldCode="DE" term="%22Amyotrophic+lateral+sclerosis%22">Amyotrophic lateral sclerosis</searchLink><br /><searchLink fieldCode="DE" term="%22Phospholipase+D%22">Phospholipase D</searchLink><br /><searchLink fieldCode="DE" term="%22Drosophila+melanogaster%22">Drosophila melanogaster</searchLink><br /><searchLink fieldCode="DE" term="%22Motor+neurons%22">Motor neurons</searchLink><br /><searchLink fieldCode="DE" term="%22Fruit+flies%22">Fruit flies</searchLink>
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  Data: Cytoplasmic mislocalization and aggregation of TDP-43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and are observed in the vast majority of both familial and sporadic cases. How these two interconnected processes are regulated on a molecular level, however, remains enigmatic. Genome-wide screens for modifiers of the ALS-associated genes TDP-43 and FUS have identified the phospholipase D (Pld) pathway as a key regulator of ALS-related phenotypes in the fruit fly Drosophila melanogaster [M. W. Kankel et al., Genetics 215, 747-766 (2020)]. Here, we report the results of our search for downstream targets of the enzymatic product of Pld, phosphatidic acid. We identify two conserved negative regulators of the cAMP/PKA signaling pathway, the phosphodiesterase dunce and the inhibitory subunit PKA-R2, as modifiers of pathogenic phenotypes resulting from overexpression of the Drosophila TDP-43 ortholog TBPH. We show that knockdown of either of these genes results in a mitigation of both TBPH aggregation and mislocalization in larval motor neuron cell bodies, as well as an amelioration of adult-onset motor defects and shortened lifespan induced by TBPH. We determine that PKA kinase activity is downstream of both TBPH and Pld and that overexpression of the PKA target CrebA can rescue TBPH mislocalization. These findings suggest a model whereby increasing cAMP/PKA signaling can ameliorate the molecular and functional effects of pathological TDP-43. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.2400732121
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        Text: English
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      – SubjectFull: Amyotrophic lateral sclerosis
        Type: general
      – SubjectFull: Phospholipase D
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      – SubjectFull: Drosophila melanogaster
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      – SubjectFull: Motor neurons
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      – SubjectFull: Fruit flies
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      – TitleFull: cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.
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              Text: 6/11/2024
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              Y: 2024
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