{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T18:20:03Z","timestamp":1767982803627,"version":"3.49.0"},"reference-count":32,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,1,30]],"date-time":"2018-01-30T00:00:00Z","timestamp":1517270400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Paul Foundation"},{"name":"Centres of Excellence in Neurodegeneration Research CoEN"},{"name":"EU Joint Programme-Neurodegenerative Disease","award":["01ED1612"],"award-info":[{"award-number":["01ED1612"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Increased expression of \u03b1\u2010synuclein can initiate its long\u2010distance brain transfer, representing a potential mechanism for pathology spreading in age\u2010related synucleinopathies, such as Parkinson's disease. In this study, the effects of overexpression\u2010induced \u03b1\u2010synuclein transfer were assessed over a 1\u2010year period after injection of viral vectors carrying human \u03b1\u2010synuclein <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> into the rat vagus nerve. This treatment causes targeted overexpression within neurons in the dorsal medulla oblongata and subsequent diffusion of the exogenous protein toward more rostral brain regions. Protein advancement and accumulation in pontine, midbrain, and forebrain areas were contingent upon continuous overexpression, because death of transduced medullary neurons resulted in cessation of spreading. Lack of sustained spreading did not prevent the development of long\u2010lasting pathological changes. Particularly remarkable were findings in the locus coeruleus, a pontine nucleus with direct connections to the dorsal medulla oblongata and greatly affected by overexpression\u2010induced transfer in this model. Data revealed progressive degeneration of catecholaminergic neurons that proceeded long beyond the time of spreading cessation. Neuronal pathology in the locus coeruleus was accompanied by pronounced microglial activation and, at later times, astrocytosis. Interestingly, microglial activation was also featured in another region reached by \u03b1\u2010synuclein transfer, the central amygdala, even in the absence of frank neurodegeneration. Thus, overexpression\u2010induced spreading, even if temporary, causes long\u2010lasting pathological consequences in brain regions distant from the site of overexpression but anatomically connected to it. Neurodegeneration may be a consequence of severe protein burden, whereas even a milder \u03b1\u2010synuclein accumulation in tissues affected by protein transfer could induce sustained microglial activation.<\/jats:p>","DOI":"10.1111\/acel.12727","type":"journal-article","created":{"date-parts":[[2018,1,31]],"date-time":"2018-01-31T02:42:46Z","timestamp":1517366566000},"source":"Crossref","is-referenced-by-count":29,"title":["Long\u2010lasting pathological consequences of overexpression\u2010induced \u03b1\u2010synuclein spreading in the rat brain"],"prefix":"10.1111","volume":"17","author":[{"given":"Raffaella","family":"Rusconi","sequence":"first","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE) Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayse","family":"Ulusoy","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE) Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helia","family":"Aboutalebi","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE) Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donato A.","family":"Di Monte","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE) Bonn 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