{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T14:37:10Z","timestamp":1784903830867,"version":"3.55.0"},"reference-count":47,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,12,4]],"date-time":"2022-12-04T00:00:00Z","timestamp":1670112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS102227"],"award-info":[{"award-number":["NS102227"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS123457"],"award-info":[{"award-number":["NS123457"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS096190"],"award-info":[{"award-number":["NS096190"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS069625"],"award-info":[{"award-number":["NS069625"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Veterans Affairs Merit Review Award","award":["NS102227"],"award-info":[{"award-number":["NS102227"]}]},{"name":"Department of Veterans Affairs Merit Review Award","award":["NS123457"],"award-info":[{"award-number":["NS123457"]}]},{"name":"Department of Veterans Affairs Merit Review Award","award":["NS096190"],"award-info":[{"award-number":["NS096190"]}]},{"name":"Department of Veterans Affairs Merit Review Award","award":["NS069625"],"award-info":[{"award-number":["NS069625"]}]},{"name":"David Johnson Family Foundation","award":["NS102227"],"award-info":[{"award-number":["NS102227"]}]},{"name":"David Johnson Family Foundation","award":["NS123457"],"award-info":[{"award-number":["NS123457"]}]},{"name":"David Johnson Family Foundation","award":["NS096190"],"award-info":[{"award-number":["NS096190"]}]},{"name":"David Johnson Family Foundation","award":["NS069625"],"award-info":[{"award-number":["NS069625"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alpha-synuclein (aSyn) is a 14 kD protein encoded by the SNCA gene that is expressed in vertebrates and normally localizes to presynaptic terminals and the nucleus. aSyn forms pathological intracellular aggregates that typify a group of important neurodegenerative diseases called synucleinopathies. Previous work in human tissue and model systems indicates that some of these aggregates can be intranuclear, but the significance of aSyn aggregation within the nucleus is not clear. We used a mouse model that develops aggregated aSyn nuclear inclusions. Using aSyn preformed fibril injections in GFP-tagged aSyn transgenic mice, we were able to induce the formation of nuclear aSyn inclusions and study their properties in fixed tissue and in vivo using multiphoton microscopy. In addition, we analyzed human synucleinopathy patient tissue to better understand this pathology. Our data demonstrate that nuclear aSyn inclusions may form through the transmission of aSyn between neurons, and these intranuclear aggregates bear the hallmarks of cytoplasmic Lewy pathology. Neuronal nuclear aSyn inclusions can form rod-like structures that do not contain actin, excluding them from being previously described nuclear actin rods. Longitudinal, in vivo multiphoton imaging indicates that certain morphologies of neuronal nuclear aSyn inclusions predict cell death within 14 days. Human multiple system atrophy cases contain neurons and glia with similar nuclear inclusions, but we were unable to detect such inclusions in Lewy body dementia cases. This study suggests that the dysregulation of a nuclear aSyn function associated with nuclear inclusion formation could play a role in the forms of neurodegeneration associated with synucleinopathy.<\/jats:p>","DOI":"10.3390\/ijms232315294","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T02:13:12Z","timestamp":1670206392000},"page":"15294","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Aggregated Alpha-Synuclein Inclusions within the Nucleus Predict Impending Neuronal Cell Death in a Mouse Model of Parkinsonism"],"prefix":"10.3390","volume":"23","author":[{"given":"Leah J.","family":"Weston","sequence":"first","affiliation":[{"name":"Department of Neurology & Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Bowman","sequence":"additional","affiliation":[{"name":"Department of Neurology & Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie R.","family":"Osterberg","sequence":"additional","affiliation":[{"name":"Department of Neurology & Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles K.","family":"Meshul","sequence":"additional","affiliation":[{"name":"Research Services, Neurocytology Laboratory, Veterans Affairs Medical Center, Portland, OR 97239, USA"},{"name":"Departments of Behavioral Neuroscience and Pathology, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall L.","family":"Woltjer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek K.","family":"Unni","sequence":"additional","affiliation":[{"name":"Department of Neurology & Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR 97239, USA"},{"name":"OHSU Parkinson Center, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2804","DOI":"10.1523\/JNEUROSCI.08-08-02804.1988","article-title":"Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal","volume":"8","author":"Maroteaux","year":"1988","journal-title":"J. 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