{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T03:30:09Z","timestamp":1768879809541,"version":"3.49.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T00:00:00Z","timestamp":1619395200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Michael J Fox Foundation"},{"name":"Hellenic Ministry of Health","award":["# 398 70\/3\/11679"],"award-info":[{"award-number":["# 398 70\/3\/11679"]}]},{"name":"Hellenic Ministry of Health","award":["FP7\/REGPOT-2008-1"],"award-info":[{"award-number":["FP7\/REGPOT-2008-1"]}]},{"DOI":"10.13039\/501100003448","name":"Hellenic General Secretariat of Research and Technology","doi-asserted-by":"crossref","award":["#650"],"award-info":[{"award-number":["#650"]}],"id":[{"id":"10.13039\/501100003448","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,7,28]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Duplication\/triplication mutations of the SNCA locus, encoding alpha-synuclein (ASYN), and loss of function mutations in Nurr1, a nuclear receptor guiding midbrain dopaminergic neuron development, are associated with familial Parkinson\u2019s disease (PD). As we age, the expression levels of these two genes in midbrain dopaminergic neurons follow opposite directions and ASYN expression increases while the expression of Nurr1 decreases. We investigated the effect of ASYN and Nurr1 age-related expression alterations in the pathogenesis of PD by coupling Nurr1 hemizygous with ASYN(s) (heterozygote) or ASYN(d) (homozygote) transgenic mice. ASYN(d)\/Nurr1+\/\u2212 (2-hit) mice, contrary to the individual genetic traits, developed phenotypes consistent with dopaminergic dysfunction. Aging \u20182-hit\u2019 mice manifested kyphosis, severe rigid paralysis, L-DOPA responsive movement impairment and cachexia and died prematurely. Pathological abnormalities of phenotypic mice included SN neuron degeneration, extensive neuroinflammation and enhanced ASYN aggregation. Mice with two wt Nurr1 alleles [ASYN(d)\/Nurr1+\/+] or with reduced ASYN load [ASYN(s)\/Nurr1+\/\u2212] did not develop the phenotype or pathology. Critically, we found that aging ASYN(d), in contrast to ASYN(s), mice suppress Nurr1-protein levels in a brain region\u2013specific manner, which in addition to Nurr1 hemizygosity is necessary to instigate PD pathogenesis. Our experiments demonstrate that ASYN-dependent PD-related pathophysiology is mediated at least in part by Nurr1 down-regulation.<\/jats:p>","DOI":"10.1093\/hmg\/ddab118","type":"journal-article","created":{"date-parts":[[2021,4,20]],"date-time":"2021-04-20T11:32:02Z","timestamp":1618918322000},"page":"1469-1483","source":"Crossref","is-referenced-by-count":16,"title":["Nurr1 repression mediates cardinal features of Parkinson\u2019s disease in \u03b1-synuclein transgenic mice"],"prefix":"10.1093","volume":"30","author":[{"given":"Maria","family":"Argyrofthalmidou","sequence":"first","affiliation":[{"name":"Center for Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Athanasios D","family":"Spathis","sequence":"additional","affiliation":[{"name":"Center for Clinical Research, Experimental Surgery and Translational Research, 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Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evangelos","family":"Sotiriou","sequence":"additional","affiliation":[{"name":"Center for Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Manousaki","sequence":"additional","affiliation":[{"name":"Center for Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celine","family":"Perier","sequence":"additional","affiliation":[{"name":"Research Institute, University Hospital Vall d'Hebron, Barcelona 08035, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioanna","family":"Papapanagiotou","sequence":"additional","affiliation":[{"name":"Center for Clinical Research, 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