{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:22:27Z","timestamp":1789647747550,"version":"4.0.0"},"posted":{"date-parts":[[2023,3,10]]},"group-title":"Neuroscience","reference-count":103,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T00:00:00Z","timestamp":1678406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of Aging","award":["AG079199"],"award-info":[{"award-number":["AG079199"]}]},{"name":"National Institute of Aging","award":["AG061175"],"award-info":[{"award-number":["AG061175"]}]},{"name":"National Institute of Aging","award":["AG085933"],"award-info":[{"award-number":["AG085933"]}]},{"name":"National Institute of Aging","award":["AG079620"],"award-info":[{"award-number":["AG079620"]}]},{"name":"National Institute of Aging","award":["AG081046"],"award-info":[{"award-number":["AG081046"]}]},{"name":"National Institute of Neurological Disease and Stroke","award":["NS129168"],"award-info":[{"award-number":["NS129168"]}]},{"name":"National Institute of Neurological Disease and Stroke","award":["NS135830"],"award-info":[{"award-number":["NS135830"]}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["MH015330"],"award-info":[{"award-number":["MH015330"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Emory National Primate Research Center","award":["OD011132"],"award-info":[{"award-number":["OD011132"]}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"crossref","award":["ES12870"],"award-info":[{"award-number":["ES12870"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100016220","name":"Georgia Clinical and Translational Science Alliance","doi-asserted-by":"crossref","award":["UL1TR002378"],"award-info":[{"award-number":["UL1TR002378"]}],"id":[{"id":"10.13039\/100016220","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The locus coeruleus (LC), the major source of norepinephrine (NE) in the brain, is among the first sites of pathology in both Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD), and it undergoes catastrophic degeneration later in both disorders. Dysregulation of the LC is thought to contribute to early behavioral symptoms of AD and PD such as anxiety and sleep disturbances, while frank LC loss promotes cognitive decline. However, the mechanisms responsible for this selective vulnerability are unknown. It has been suggested that neuromelanin (NM) pigment contributes to LC susceptibility, but a causal relationship has been difficult to test because rodents do not naturally produce NM. Here, we report that viral-mediated expression of human tyrosinase-induced pigmentation in male and female mouse LC neurons recapitulated key macroscopic and ultrastructural features of natural primate NM. One week of NM accumulation resulted in LC neuron hyperactivity, reduced tissue NE levels, transcriptional changes, and anxiety-like behavior. By 6 weeks, NM accumulation was associated with severe cell-autonomous LC neuron degeneration, neuroinflammation, and microglial engulfment of the pigment granules, while the anxiety-like behavior abated. These phenotypes are reminiscent of LC dysfunction and cell death in AD and PD, validating this model for studying the consequences of NM accumulation in the LC as it relates to neurodegenerative diseases.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD) are the most common neurodegenerative diseases worldwide. Because therapies that cure or prevent their progression are lacking, research is focused on the identifying the earliest signs of disease as targets for diagnosis and treatment. The locus coeruleus (LC), the main source of norepinephrine (NE) in the brain, is one of the first brain regions affected in both AD and PD. Early on, LC dysregulation promotes behavioral symptoms of AD and PD, while its subsequent degeneration accelerates disease progression. Here we identify neuromelanin (NM) pigment as an LC vulnerability factor that induces neuronal hyperactivity followed by cell death. Approaches that mitigate NM accumulation and toxicity may target the earliest phases of neurodegenerative disease.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.03.07.530845","type":"posted-content","created":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T18:25:27Z","timestamp":1678472727000},"source":"Crossref","is-referenced-by-count":16,"title":["Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus"],"prefix":"10.64898","author":[{"given":"Leslie","family":"Hassanein","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Mulvey","sequence":"additional","affiliation":[{"name":"Department of Genetics and Department of Psychiatry, Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD 21205, USA"},{"name":"Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harris E.","family":"Blankenship","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Tish","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anu","family":"Korukonda","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. 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