{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:36:57Z","timestamp":1787027817291,"version":"build-2736575974"},"reference-count":60,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"M. J. Fox Foundation","award":["R01 EY035539"],"award-info":[{"award-number":["R01 EY035539"]}]},{"name":"National Eye Institute","award":["R01 EY035539"],"award-info":[{"award-number":["R01 EY035539"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>This study investigated the therapeutic potential of the nuclear retinoid X receptor (RXR) in mitigating the progression of alpha-synucleinopathies (\u03b1SNPs), particularly in Parkinson\u2019s disease (PD). PD-like pathology in mice was successfully induced through the co-delivery of AAV expressing human \u03b1-synuclein (\u03b1S) and \u03b1S 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 PPAR\u03b1 and NURR1\u2014proteins essential for neuronal survival\u2014along with elevated expression of IBA1 and GFAP, markers of microglial activation and astrocytic gliosis, respectively, are associated with the pathogenesis of Parkinson\u2019s disease. AAV-mediated overexpression of human RXR\u03b1 demonstrated preservation of TH+ neurons, prevention of DA decline, and attenuation of \u03b1S 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 PPAR\u03b1 and NURR1. These findings suggest that RXR\u03b1 upregulation promotes neuroprotection by mitigating \u03b1SNPs 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.<\/jats:p>","DOI":"10.3390\/cells14100685","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T08:20:23Z","timestamp":1746778823000},"page":"685","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Retinoid X Receptor as a Therapeutic Target to Treat Neurological Disorders Associated with \u03b1-Synucleinopathy"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9244-1505","authenticated-orcid":false,"given":"Assylbek","family":"Zhylkibayev","sequence":"first","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2038-481X","authenticated-orcid":false,"given":"Christopher R.","family":"Starr","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, University of Alabama, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8587-4131","authenticated-orcid":false,"given":"M. Iqbal","family":"Hossain","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, University of Alabama, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaida A.","family":"Andrabi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, School of Medicine, University of Alabama, Birmingham, AL 35294, USA"},{"name":"Department of Neurology, School of Medicine, University of Alabama, Birmingham, AL 35205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria B.","family":"Grant","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, University of Alabama, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0085-0403","authenticated-orcid":false,"given":"Venkatram R.","family":"Atigadda","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9060-856X","authenticated-orcid":false,"given":"Marina S.","family":"Gorbatyuk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg S.","family":"Gorbatyuk","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1002\/gps.1738","article-title":"Patients with Lewy body dementia use more resources than those with Alzheimer\u2019s disease","volume":"22","author":"Bostrom","year":"2007","journal-title":"Int. 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