Retinoid X Receptor as a Therapeutic Target to Treat Neurological Disorders Associated with α-Synucleinopathy
This study investigated the therapeutic potential of the nuclear retinoid X receptor (RXR) in mitigating the progression of alpha-synucleinopathies (αSNPs), particularly in Parkinson’s disease (PD). PD-like pathology in mice was successfully induced through the co-delivery of AAV expressing human α-...
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2025-05-01
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| author | Assylbek Zhylkibayev Christopher R. Starr M. Iqbal Hossain Sandeep Kumar Shaida A. Andrabi Maria B. Grant Venkatram R. Atigadda Marina S. Gorbatyuk Oleg S. Gorbatyuk |
| author_facet | Assylbek Zhylkibayev Christopher R. Starr M. Iqbal Hossain Sandeep Kumar Shaida A. Andrabi Maria B. Grant Venkatram R. Atigadda Marina S. Gorbatyuk Oleg S. Gorbatyuk |
| author_sort | Assylbek Zhylkibayev |
| collection | DOAJ |
| description | This study investigated the therapeutic potential of the nuclear retinoid X receptor (RXR) in mitigating the progression of alpha-synucleinopathies (αSNPs), particularly in Parkinson’s disease (PD). PD-like pathology in mice was successfully induced through the co-delivery of AAV expressing human α-synuclein (αS) and αS preformed fibrils (PFFs) into the substantia nigra pars compacta (SNpc). Significant increases in Lewy body (LB)-like inclusions, loss of tyrosine hydroxylase-positive (TH+) neurons, and reductions in dopamine (DA) levels in the striatum were observed. Additionally, diminished levels of PPARα and NURR1—proteins essential for neuronal survival—along with elevated expression of IBA1 and GFAP, markers of microglial activation and astrocytic gliosis, respectively, are associated with the pathogenesis of Parkinson’s disease. AAV-mediated overexpression of human RXRα demonstrated preservation of TH+ neurons, prevention of DA decline, and attenuation of αS accumulation. Furthermore, RXR-treated PD brains showed a reduced number of GFAP+ and Iba1+ cells, decreased GFAP+ and IBA1+ immunoreactivity, and fewer and less widespread LB-like aggregates. RXR overexpression also enhanced the production of PPARα and NURR1. These findings suggest that RXRα upregulation promotes neuroprotection by mitigating αSNPs and chronic neuroinflammation, a major contributor to PD progression. This research underscores the therapeutic potential of targeting nuclear receptors, such as RXR, in neurodegenerative diseases like PD. |
| format | Article |
| id | doaj-art-60abd6cd488a401490df17d42fba8a21 |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-60abd6cd488a401490df17d42fba8a212025-08-20T03:47:52ZengMDPI AGCells2073-44092025-05-01141068510.3390/cells14100685Retinoid X Receptor as a Therapeutic Target to Treat Neurological Disorders Associated with α-SynucleinopathyAssylbek Zhylkibayev0Christopher R. Starr1M. Iqbal Hossain2Sandeep Kumar3Shaida A. Andrabi4Maria B. Grant5Venkatram R. Atigadda6Marina S. Gorbatyuk7Oleg S. Gorbatyuk8Department of Biochemistry, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USADepartment of Ophthalmology, School of Medicine, University of Alabama, Birmingham, AL 35233, USADepartment of Pharmacology and Toxicology, School of Medicine, University of Alabama, Birmingham, AL 35294, USADepartment of Biochemistry, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USADepartment of Pharmacology and Toxicology, School of Medicine, University of Alabama, Birmingham, AL 35294, USADepartment of Ophthalmology, School of Medicine, University of Alabama, Birmingham, AL 35233, USADepartment of Dermatology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35233, USADepartment of Biochemistry, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USADepartment of Translational Neuroscience, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USAThis study investigated the therapeutic potential of the nuclear retinoid X receptor (RXR) in mitigating the progression of alpha-synucleinopathies (αSNPs), particularly in Parkinson’s disease (PD). PD-like pathology in mice was successfully induced through the co-delivery of AAV expressing human α-synuclein (αS) and αS preformed fibrils (PFFs) into the substantia nigra pars compacta (SNpc). Significant increases in Lewy body (LB)-like inclusions, loss of tyrosine hydroxylase-positive (TH+) neurons, and reductions in dopamine (DA) levels in the striatum were observed. Additionally, diminished levels of PPARα and NURR1—proteins essential for neuronal survival—along with elevated expression of IBA1 and GFAP, markers of microglial activation and astrocytic gliosis, respectively, are associated with the pathogenesis of Parkinson’s disease. AAV-mediated overexpression of human RXRα demonstrated preservation of TH+ neurons, prevention of DA decline, and attenuation of αS accumulation. Furthermore, RXR-treated PD brains showed a reduced number of GFAP+ and Iba1+ cells, decreased GFAP+ and IBA1+ immunoreactivity, and fewer and less widespread LB-like aggregates. RXR overexpression also enhanced the production of PPARα and NURR1. These findings suggest that RXRα upregulation promotes neuroprotection by mitigating αSNPs and chronic neuroinflammation, a major contributor to PD progression. This research underscores the therapeutic potential of targeting nuclear receptors, such as RXR, in neurodegenerative diseases like PD.https://www.mdpi.com/2073-4409/14/10/685α-synucleinopathyParkinson’s diseaseretinoid X receptorα-synucleinLewy bodydopamine |
| spellingShingle | Assylbek Zhylkibayev Christopher R. Starr M. Iqbal Hossain Sandeep Kumar Shaida A. Andrabi Maria B. Grant Venkatram R. Atigadda Marina S. Gorbatyuk Oleg S. Gorbatyuk Retinoid X Receptor as a Therapeutic Target to Treat Neurological Disorders Associated with α-Synucleinopathy Cells α-synucleinopathy Parkinson’s disease retinoid X receptor α-synuclein Lewy body dopamine |
| title | Retinoid X Receptor as a Therapeutic Target to Treat Neurological Disorders Associated with α-Synucleinopathy |
| title_full | Retinoid X Receptor as a Therapeutic Target to Treat Neurological Disorders Associated with α-Synucleinopathy |
| title_fullStr | Retinoid X Receptor as a Therapeutic Target to Treat Neurological Disorders Associated with α-Synucleinopathy |
| title_full_unstemmed | Retinoid X Receptor as a Therapeutic Target to Treat Neurological Disorders Associated with α-Synucleinopathy |
| title_short | Retinoid X Receptor as a Therapeutic Target to Treat Neurological Disorders Associated with α-Synucleinopathy |
| title_sort | retinoid x receptor as a therapeutic target to treat neurological disorders associated with α synucleinopathy |
| topic | α-synucleinopathy Parkinson’s disease retinoid X receptor α-synuclein Lewy body dopamine |
| url | https://www.mdpi.com/2073-4409/14/10/685 |
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