{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:52:23Z","timestamp":1791852743382,"version":"4.3.4"},"reference-count":68,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013015","name":"cedars-sinai medical center","doi-asserted-by":"publisher","award":["231627"],"award-info":[{"award-number":["231627"]}],"id":[{"id":"10.13039\/100013015","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Dopaminergic neuron degeneration in the midbrain plays a pivotal role in motor symptoms associated with Parkinson\u2019s disease. However, non-motor symptoms of Parkinson\u2019s disease and post-mortem histopathology confirm dysfunction in other brain areas, including the locus coeruleus and its associated neurotransmitter norepinephrine. Here, we investigate the role of central norepinephrine-producing neurons in Parkinson\u2019s disease by chronically stimulating catecholaminergic neurons in the locus coeruleus using chemogenetic manipulation. We show that norepinephrine neurons send complex axonal projections to the dopaminergic neurons in the substantia nigra, confirming physical communication between these regions. Furthermore, we demonstrate that increased activity of norepinephrine neurons is protective against dopaminergic neuronal depletion in human \u03b1-syn A53T missense mutation over-expressing mice and prevents motor dysfunction in these mice. Remarkably, elevated norepinephrine neurons action fails to alleviate \u03b1-synuclein aggregation and microgliosis in the substantia nigra suggesting the presence of an alternate neuroprotective mechanism. The beneficial effects of high norepinephrine neuron activity might be attributed to the action of norepinephrine on dopaminergic neurons, as recombinant norepinephrine treatment increased primary dopaminergic neuron cultures survival and neurite sprouting. Collectively, our results suggest a neuroprotective mechanism where noradrenergic neurons activity preserves the integrity of dopaminergic neurons, which prevents synucleinopathy-dependent loss of these cells.<\/jats:p>","DOI":"10.1371\/journal.pone.0263074","type":"journal-article","created":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T17:26:46Z","timestamp":1647970006000},"page":"e0263074","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":23,"title":["Sustained chemogenetic activation of locus coeruleus norepinephrine neurons promotes dopaminergic neuron survival in synucleinopathy"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1273-5341","authenticated-orcid":true,"given":"Predrag","family":"Jovanovic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yidan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Philippe","family":"Vit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Novinbakht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Morones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elliot","family":"Hogg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Tagliati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3535-3407","authenticated-orcid":true,"given":"Celine E.","family":"Riera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,3,22]]},"reference":[{"key":"pone.0263074.ref001","first-page":"12","article-title":"\u03b1-Synuclein and Noradrenergic Modulation of Immune Cells in Parkinson\u2019s Disease Pathogenesis","author":"LM Butkovich","year":"2018","journal-title":"Front Neurosci"},{"key":"pone.0263074.ref002","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/334345a0","article-title":"Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson\u2019s disease","volume":"334","author":"E Hirsch","year":"1988","journal-title":"Nature"},{"key":"pone.0263074.ref003","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1136\/jnnp.23.4.283","article-title":"The Distribution of Lewy Bodies in the Central and Autonomic Nervous Systems in Idiopathic Paralysis Agitans","volume":"23","author":"WADH Jager","year":"1960","journal-title":"Journal of Neurology, Neurosurgery & Psychiatry"},{"key":"pone.0263074.ref004","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/42166","article-title":"\u03b1-Synuclein in Lewy bodies","volume":"388","author":"MG Spillantini","year":"1997","journal-title":"Nature"},{"key":"pone.0263074.ref005","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/ncpneuro0126","article-title":"The genetics of Parkinson disease: Implications for neurological care","volume":"2","author":"C Klein","year":"2006","journal-title":"Nat Clin Pract Neurol"},{"key":"pone.0263074.ref006","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0896-6273(02)00682-7","article-title":"Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein","volume":"34","author":"BI Giasson","year":"2002","journal-title":"Neuron"},{"key":"pone.0263074.ref007","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1126\/science.287.5456.1265","article-title":"Dopaminergic Loss and Inclusion Body Formation in \u03b1-Synuclein Mice: Implications for Neurodegenerative Disorders","volume":"287","author":"E Masliah","year":"2000","journal-title":"Science"},{"key":"pone.0263074.ref008","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1126\/science.1195227","article-title":"Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro","volume":"329","author":"J Burr\u00e9","year":"2010","journal-title":"Science"},{"key":"pone.0263074.ref009","doi-asserted-by":"crossref","first-page":"a009399","DOI":"10.1101\/cshperspect.a009399","article-title":"\u03b1-Synuclein in Parkinson\u2019s disease","volume":"2","author":"L. 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