{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T06:07:47Z","timestamp":1788847667548,"version":"build-2803163510"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>\n                    Parkinson\u2019s disease is one of a group of diseases collectively termed \u03b1-synucleinopathies, all of which are characterized by abnormal accumulation of toxic \u03b1-synuclein (\u03b1-syn) assemblies which are thought to follow a prion-like propagation model and drive neuronal death. Both intrinsic strain properties and the genetic background of affected individuals are hypothesized to influence \u03b1-syn aggregate accumulation, propagation, and extracellular release. As such, the aim of this study is to characterize how different genetic backgrounds modulate \u03b1-syn aggregate accumulation and release in response to treatment with different \u03b1-syn strains. iPSC-derived neurons from five different groups were employed (healthy non-PD controls (NPC), idiopathic PD (iPD),\n                    <jats:italic>GBA1<\/jats:italic>\n                    N370S,\n                    <jats:italic>LRRK2<\/jats:italic>\n                    G2019S and\n                    <jats:italic>SNCA<\/jats:italic>\n                    A53T) (\n                    <jats:italic>n<\/jats:italic>\n                    = 15 cell lines, three lines per group). Individual aggregates in conditioned medium (CM) were measured using a single-particle detection system to quantify released \u03b1-syn species and assess strain persistence across genotype groups. Seed amplification assay (SAA) was then applied and linear discriminant analysis (LDA) of single particle properties from CM of \u03b1-syn fibril-treated neurons was used to discriminate between groups. \u03b1-Syn released into CM showed strain persistence in\n                    <jats:italic>LRRK2<\/jats:italic>\n                    G2019S and\n                    <jats:italic>GBA1<\/jats:italic>\n                    N370S genotype groups, while\n                    <jats:italic>SNCA<\/jats:italic>\n                    A53T neurons exhibited evidence of strain remodeling. Interestingly, amplification-response \u0394-feature analysis of single particle properties showed group discrimination beyond either pre- or post- amplification measurements independently, reaching a maximum LOO-CV accuracy of 66.7% (3.3 \u00d7 chance level) at day 10 post-treatment in CM from fibrils-treated neurons. These findings indicate that genotype-specific cellular responses differentially shape the structural properties of released \u03b1-syn in a manner that determines amplification responses, enabling inter-group discrimination at the single-molecule level.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2026.1917981","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T05:35:33Z","timestamp":1788845733000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Seed amplification of released alpha-synuclein strains reveals genotype-specific differences in Parkinson\u2019s disease neurons"],"prefix":"10.3389","volume":"18","author":[{"given":"Jessica","family":"Chedid","sequence":"first","affiliation":[{"name":"Macquarie Medical School, Faculty of Health and Human Sciences, Macquarie University","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, University of Sydney","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Law","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lachlan","family":"Thompson","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"Gambin","sequence":"additional","affiliation":[{"name":"EMBL Australia Node for Single Molecule Science and School of Biomedical Sciences, Faculty of Medicine, The University of New South Wales","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Sierecki","sequence":"additional","affiliation":[{"name":"EMBL Australia Node for Single Molecule Science and School of Biomedical Sciences, Faculty of Medicine, The University of New South Wales","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Dzamko","sequence":"additional","affiliation":[{"name":"Macquarie Medical School, Faculty of Health and Human Sciences, Macquarie University","place":["Sydney, NSW, Australia"]},{"name":"School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, University of Sydney","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.neuron.2019.10.010","article-title":"Amyloid-Beta (A\u03b2) plaques promote seeding and spreading of alpha-synuclein and tau in a mouse model of lewy body disorders with A\u03b2 pathology.","volume":"105","author":"Bassil","year":"2020","journal-title":"Neuron"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2575","DOI":"10.1038\/ncomms3575","article-title":"Structural and functional characterization of two alpha-synuclein strains.","volume":"4","author":"Bousset","year":"2013","journal-title":"Nat. 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