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ORIGINAL RESEARCH article

Front. Mol. Neurosci.
Sec. Brain Disease Mechanisms
Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1524044

The effect of AKT inhibition in α-synuclein-dependent neurodegeneration

Provisionally accepted
Bedri Ranxhi Bedri Ranxhi 1Zoya R Bangash Zoya R Bangash 1Zachary M Chbihi Zachary M Chbihi 1Sokol V Todi Sokol V Todi 1,2Peter A Lewitt Peter A Lewitt 1,2,3*Wei-Ling Tsou Wei-Ling Tsou 1*
  • 1 Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan, United States
  • 2 Department of Neurology, School of Medicine, Wayne State University, Detroit, Michigan, United States
  • 3 Department of Neurology, Henry Ford Health Systems, Detroit, United States

The final, formatted version of the article will be published soon.

    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.

    Keywords: α-Synuclein, Synucleinopathy, Akt, NF-κB, neurodegenerative disease, Parkinson's disease, Proteinopathy, Protein misfolding disorders

    Received: 07 Nov 2024; Accepted: 08 Jan 2025.

    Copyright: © 2025 Ranxhi, Bangash, Chbihi, Todi, Lewitt and Tsou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Peter A Lewitt, Department of Neurology, School of Medicine, Wayne State University, Detroit, MI 48201, Michigan, United States
    Wei-Ling Tsou, Department of Pharmacology, School of Medicine, Wayne State University, Detroit, 48201, Michigan, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.