{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:21:21Z","timestamp":1768519281733,"version":"3.49.0"},"posted":{"date-parts":[[2024,12,20]]},"group-title":"Neuroscience","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T00:00:00Z","timestamp":1734652800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,12,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mutations in leucine-rich repeat kinase 2 (\n                  <jats:italic>LRRK2<\/jats:italic>\n                  ) are the most common cause of familial and sporadic Parkinson\u2019s disease (PD). While the clinical features of\n                  <jats:italic>LRRK2<\/jats:italic>\n                  -PD patients resemble those of typical PD, there are significant differences in the pathological findings. The pathological hallmark of definite PD is the presence of \u03b1-synuclein (\u03b1SYN)-positive Lewy-related pathology; however, approximately half of\n                  <jats:italic>LRRK2<\/jats:italic>\n                  -PD cases do not have Lewy-related pathology. Lewy-related pathology is a late-stage \u03b1SYN aggregation that can be visualized with hematoxylin and eosin stains or conventional immunohistochemistry (IHC). Increasing evidence has indicated that \u03b1SYN oligomers, which represent the early-stage of \u03b1SYN aggregation, may have neurotoxicity. Visualization of \u03b1SYN oligomers requires specialized staining techniques, such as \u03b1SYN-proximity ligation assay (PLA). The distribution and severity of \u03b1SYN oligomers in the human brain of\n                  <jats:italic>LRRK2<\/jats:italic>\n                  -PD patients remain unknown. In this study, we performed phosphorylated \u03b1SYN-IHC and \u03b1SYN-PLA staining on postmortem brain sections of patients with three pathogenic LRRK2 mutants: p.G2019S (n=5), p.I2020T (n=5), and p.R1441C (n=4). The severity of Lewy-related pathology and \u03b1SYN oligomers were assessed semi-quantitatively in the brainstem, limbic lobe, basal ganglia, and cerebral cortex. \u03b1SYN oligomers were detected in\n                  <jats:italic>LRRK2<\/jats:italic>\n                  -PD cases even in cases without Lewy-related pathology; a negative correlation was observed between Lewy-related pathology and \u03b1SYN oligomers (r=-0.26 [-0.39, -0.12]; P&lt;0.0001). Our findings suggest that \u03b1SYN oligomers may represent a common pathological feature of\n                  <jats:italic>LRRK2<\/jats:italic>\n                  -PD. Notably, patients harboring p.G2019S and p.I2020T had significantly higher levels of \u03b1SYN oligomers in those without Lewy-related pathology compared to those with Lewy-related pathology. These cases also had a trend toward shorter disease duration. These results imply that in\n                  <jats:italic>LRRK2<\/jats:italic>\n                  -PD, \u03b1SYN oligomers may initially accumulate in the brain but do not progress to form Lewy-related pathology. The present study suggests that targeting \u03b1SYN oligomers may be a therapeutic strategy for\n                  <jats:italic>LRRK2<\/jats:italic>\n                  -PD even if there is no Lewy-related pathology.\n                <\/jats:p>","DOI":"10.1101\/2024.12.18.629265","type":"posted-content","created":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T03:59:38Z","timestamp":1734753578000},"source":"Crossref","is-referenced-by-count":1,"title":["Widespread Distribution of \u03b1-Synuclein Oligomers in\n                  <i>LRRK2<\/i>\n                  -related Parkinson\u2019s Disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9683-5966","authenticated-orcid":false,"given":"Hiroaki","family":"Sekiya","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lukas","family":"Franke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariko","family":"Takata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4978-5382","authenticated-orcid":false,"given":"Katsuya","family":"Nishida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naonobu","family":"Futamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuko","family":"Hasegawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5300-8589","authenticated-orcid":false,"given":"Hisatomo","family":"Kowa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4813-756X","authenticated-orcid":false,"given":"Owen 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