The effect of AKT inhibition in α-synuclein-dependent neurodegeneration
Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting millions of individuals worldwide. A hallmark of PD pathology is the accumulation of α-synuclein (α-Syn), a small protein known to support neuronal development and function. However, in PD, α-Syn cumulatively misfolds int...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2025.1524044/full |
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| author | Bedri Ranxhi Zoya R. Bangash Zachary M. Chbihi Sokol V. Todi Sokol V. Todi Peter A. LeWitt Peter A. LeWitt Peter A. LeWitt Wei-Ling Tsou |
| author_facet | Bedri Ranxhi Zoya R. Bangash Zachary M. Chbihi Sokol V. Todi Sokol V. Todi Peter A. LeWitt Peter A. LeWitt Peter A. LeWitt Wei-Ling Tsou |
| author_sort | Bedri Ranxhi |
| collection | DOAJ |
| description | Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting millions of individuals worldwide. A hallmark of PD pathology is the accumulation of α-synuclein (α-Syn), a small protein known to support neuronal development and function. However, in PD, α-Syn cumulatively misfolds into toxic aggregates that disrupt cellular processes and contribute to neuronal damage and neurodegeneration. Previous studies implicated the AKT signaling pathway in α-Syn toxicity in cellular models of PD, suggesting AKT as a potential therapeutic target. Here, we investigated the effect of AKT inhibition in a Drosophila model of synucleinopathy. We observed that administration of the AKT inhibitor, A-443654 led to mild improvements in both survival and motor function in flies expressing human α-Syn. Genetic studies revealed that reduction of AKT levels decreased α-Syn protein levels, concomitant with improved physiological outcomes. The protective effects of AKT reduction appear to operate through the fly ortholog of NF-κB, Relish, suggesting a link between AKT and NF-κB in regulating α-Syn levels. These findings highlight the AKT cascade as a potential therapeutic target for synucleinopathies and provide insights into mechanisms that could be utilized to reduce α-Syn toxicity in PD and related disorders, such as multiple system atrophy. |
| format | Article |
| id | doaj-art-30b3073aea5e4c2b86f48297b4452b48 |
| institution | Kabale University |
| issn | 1662-5099 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj-art-30b3073aea5e4c2b86f48297b4452b482025-02-05T07:32:23ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992025-02-011810.3389/fnmol.2025.15240441524044The effect of AKT inhibition in α-synuclein-dependent neurodegenerationBedri Ranxhi0Zoya R. Bangash1Zachary M. Chbihi2Sokol V. Todi3Sokol V. Todi4Peter A. LeWitt5Peter A. LeWitt6Peter A. LeWitt7Wei-Ling Tsou8Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United StatesDepartment of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United StatesDepartment of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United StatesDepartment of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United StatesDepartment of Neurology, Wayne State University School of Medicine, Detroit, MI, United StatesDepartment of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United StatesDepartment of Neurology, Wayne State University School of Medicine, Detroit, MI, United StatesDepartment of Neurology, Henry Ford Health Systems, Detroit, MI, United StatesDepartment of Pharmacology, Wayne State University School of Medicine, Detroit, MI, United StatesParkinson’s disease (PD) is a progressive neurodegenerative disorder affecting millions of individuals worldwide. A hallmark of PD pathology is the accumulation of α-synuclein (α-Syn), a small protein known to support neuronal development and function. However, in PD, α-Syn cumulatively misfolds into toxic aggregates that disrupt cellular processes and contribute to neuronal damage and neurodegeneration. Previous studies implicated the AKT signaling pathway in α-Syn toxicity in cellular models of PD, suggesting AKT as a potential therapeutic target. Here, we investigated the effect of AKT inhibition in a Drosophila model of synucleinopathy. We observed that administration of the AKT inhibitor, A-443654 led to mild improvements in both survival and motor function in flies expressing human α-Syn. Genetic studies revealed that reduction of AKT levels decreased α-Syn protein levels, concomitant with improved physiological outcomes. The protective effects of AKT reduction appear to operate through the fly ortholog of NF-κB, Relish, suggesting a link between AKT and NF-κB in regulating α-Syn levels. These findings highlight the AKT cascade as a potential therapeutic target for synucleinopathies and provide insights into mechanisms that could be utilized to reduce α-Syn toxicity in PD and related disorders, such as multiple system atrophy.https://www.frontiersin.org/articles/10.3389/fnmol.2025.1524044/fullα-synucleinsynucleinopathyAKTNF-κBneurodegenerative diseaseParkinson’s disease |
| spellingShingle | Bedri Ranxhi Zoya R. Bangash Zachary M. Chbihi Sokol V. Todi Sokol V. Todi Peter A. LeWitt Peter A. LeWitt Peter A. LeWitt Wei-Ling Tsou The effect of AKT inhibition in α-synuclein-dependent neurodegeneration Frontiers in Molecular Neuroscience α-synuclein synucleinopathy AKT NF-κB neurodegenerative disease Parkinson’s disease |
| title | The effect of AKT inhibition in α-synuclein-dependent neurodegeneration |
| title_full | The effect of AKT inhibition in α-synuclein-dependent neurodegeneration |
| title_fullStr | The effect of AKT inhibition in α-synuclein-dependent neurodegeneration |
| title_full_unstemmed | The effect of AKT inhibition in α-synuclein-dependent neurodegeneration |
| title_short | The effect of AKT inhibition in α-synuclein-dependent neurodegeneration |
| title_sort | effect of akt inhibition in α synuclein dependent neurodegeneration |
| topic | α-synuclein synucleinopathy AKT NF-κB neurodegenerative disease Parkinson’s disease |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2025.1524044/full |
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