{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:11:44Z","timestamp":1787022704429,"version":"build-2736575974"},"reference-count":64,"publisher":"Society for Neuroscience","issue":"42","license":[{"start":{"date-parts":[[2016,4,21]],"date-time":"2016-04-21T00:00:00Z","timestamp":1461196800000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2015,10,21]]},"abstract":"<jats:p>\n                    \u03b1-synuclein, a protein enriched in Lewy bodies and highly implicated in neurotoxicity in Parkinson's disease, is distributed both at nerve terminals and in the cell nucleus. Here we show that a nuclear derivative of \u03b1-synuclein induces more pronounced changes at the gene expression level in mouse primary dopamine (DA) neurons compared to a derivative that is excluded from the nucleus. Moreover, by RNA sequencing we analyzed the extent of genome-wide effects on gene expression resulting from expression of human \u03b1-synuclein in primary mouse DA neurons. The results implicated the transcription factor Nurr1 as a key dysregulated target of \u03b1-synuclein toxicity. Forced Nurr1 expression restored the expression of hundreds of dysregulated genes in primary DA neurons expressing \u03b1-synuclein, and therefore prompted us to test the possibility that Nurr1 can be pharmacologically targeted by bexarotene, a ligand for the retinoid X receptor that forms heterodimers with Nurr1. Although our data demonstrated that bexarotene was ineffective in neuroprotection in rats\n                    <jats:italic>in vivo<\/jats:italic>\n                    , the results revealed that bexarotene has the capacity to coregulate subsets of Nurr1 target genes including the receptor tyrosine kinase subunit Ret. Moreover, bexarotene was able to restore dysfunctional Ret-dependent neurotrophic signaling in \u03b1-synuclein-overexpressing mouse DA neurons. These data highlight the role of the Nurr1\u2013Ret signaling pathway as a target of \u03b1-synuclein toxicity and suggest that retinoid X receptor ligands with appropriate pharmacological properties could have therapeutic potential in Parkinson's disease.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>\n                    How \u03b1-synuclein, a protein enriched in Lewy bodies in Parkinson's disease, is causing neuropathology in dopamine neurons remains unclear. This study elucidated how \u03b1-synuclein is influencing gene expression and how Nurr1, a transcription factor known to protect dopamine neurons against \u03b1-synuclein toxicity, can counteract these effects. Moreover, given the protective role of Nurr1, this study also investigated how Nurr1 could be pharmacologically targeted via bexarotene, a ligand of Nurr1's heterodimerization partner retinoid X receptor (RXR). The results showed that RXR ligands could increase neurotrophic signaling, but provided a mixed picture of its potential in a Parkinson's disease rat model\n                    <jats:italic>in vivo<\/jats:italic>\n                    . However, this study clearly emphasized Nurr1's neuroprotective role and indicated that other RXR ligands could have therapeutic potential in Parkinson's disease.\n                  <\/jats:p>","DOI":"10.1523\/jneurosci.1155-15.2015","type":"journal-article","created":{"date-parts":[[2015,10,22]],"date-time":"2015-10-22T03:53:55Z","timestamp":1445486035000},"page":"14370-14385","source":"Crossref","is-referenced-by-count":64,"title":["Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate \u03b1-Synuclein Disrupted Gene 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