{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T17:52:00Z","timestamp":1780509120808,"version":"3.54.1"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T00:00:00Z","timestamp":1684540800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T00:00:00Z","timestamp":1684540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100015098","name":"Seoul Metropolitan Government Seoul National University Boramae Medical Center","doi-asserted-by":"publisher","award":["02-2020-2"],"award-info":[{"award-number":["02-2020-2"]}],"id":[{"id":"10.13039\/501100015098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["NRF-2018R1A5A2025964"],"award-info":[{"award-number":["NRF-2018R1A5A2025964"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Parkinson\u2019s disease (PD) is a neurodegenerative disorder characterized by the aggregation of misfolded \u03b1-synuclein and progressive spreading of the aggregates from a few discrete regions to wider brain regions. Although PD has been classically considered a movement disorder, a large body of clinical evidence has revealed the progressive occurrence of non-motor symptoms. Patients present visual symptoms in the initial stages of the disease, and accumulation of phospho-\u03b1-synuclein, dopaminergic neuronal loss, and retinal thinning has been observed in the retinas of PD patients. Based on such human data, we hypothesized that \u03b1-synuclein aggregation can initiate in the retina and spread to the brain through the visual pathway. Here, we demonstrate accumulation of \u03b1-synuclein in the retinas and brains of naive mice after intravitreal injection of \u03b1-synuclein preformed fibrils (PFFs). Histological analyses showed deposition of phospho-\u03b1-synuclein inclusions within the retina 2\u00a0months after injection, with increased oxidative stress leading to loss of retinal ganglion cells and dopaminergic dysfunction. In addition, we found accumulation of phospho-\u03b1-synuclein in cortical areas with accompanying neuroinflammation after 5\u00a0months. Collectively, our findings suggest that retinal synucleinopathy lesions initiated by intravitreal injection of \u03b1-synuclein PFFs spread to various brain regions through the visual pathway in mice.<\/jats:p>","DOI":"10.1186\/s40478-023-01575-0","type":"journal-article","created":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T10:02:47Z","timestamp":1684576967000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Retina-to-brain spreading of \u03b1-synuclein after intravitreal injection of preformed fibrils"],"prefix":"10.1186","volume":"11","author":[{"given":"Dayana","family":"P\u00e9rez-Acu\u00f1a","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ka Hyun","family":"Rhee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soo Jean","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeeyun","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jee-Young","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5155-5335","authenticated-orcid":false,"given":"Seung-Jae","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,20]]},"reference":[{"key":"1575_CR1","doi-asserted-by":"publisher","first-page":"e1003","DOI":"10.1212\/WNL.0000000000006157","volume":"91","author":"J Ahn","year":"2018","unstructured":"Ahn J, Lee J-Y, Kim TW, Yoon EJ, Oh S, Kim YK, Kim J-M, Woo SJ, Kim KW, Jeon B (2018) Retinal thinning associates with nigral dopaminergic loss in de novo Parkinson disease. Neurology 91:e1003. https:\/\/doi.org\/10.1212\/WNL.0000000000006157","journal-title":"Neurology"},{"key":"1575_CR2","doi-asserted-by":"publisher","DOI":"10.4061\/2011\/908306","author":"RA Armstrong","year":"2011","unstructured":"Armstrong RA (2011) Visual symptoms in Parkinson\u2019s disease. Parkinson\u2019s Disease. https:\/\/doi.org\/10.4061\/2011\/908306","journal-title":"Parkinson\u2019s Disease"},{"key":"1575_CR3","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1038\/s12276-022-00789-x","volume":"54","author":"E-J Bae","year":"2022","unstructured":"Bae E-J, Choi M, Kim JT, Kim D-K, Jung MK, Kim C, Kim T-K, Lee JS, Jung BC, Shin SJ et al (2022) TNF-\u03b1 promotes \u03b1-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis. Exp Mol Med 54:788\u2013800. https:\/\/doi.org\/10.1038\/s12276-022-00789-x","journal-title":"Exp Mol Med"},{"key":"1575_CR4","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.neulet.2014.04.027","volume":"571","author":"TG Beach","year":"2014","unstructured":"Beach TG, Carew J, Serrano G, Adler CH, Shill HA, Sue LI, Sabbagh MN, Akiyama H, Cuenca N, Consortium APSD (2014) Phosphorylated alpha-synuclein-immunoreactive retinal neuronal elements in Parkinson\u2019s disease subjects. Neurosci Lett 571:34\u201338. https:\/\/doi.org\/10.1016\/j.neulet.2014.04.027","journal-title":"Neurosci Lett"},{"key":"1575_CR5","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1002\/ana.24182","volume":"75","author":"I Bodis-Wollner","year":"2014","unstructured":"Bodis-Wollner I, Kozlowski PB, Glazman S, Miri S (2014) \u03b1-synuclein in the inner retina in parkinson disease. Ann Neurol 75:964\u2013966. https:\/\/doi.org\/10.1002\/ana.24182","journal-title":"Ann Neurol"},{"key":"1575_CR6","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/s0197-4580(02)00065-9","volume":"24","author":"H Braak","year":"2003","unstructured":"Braak H, Del Tredici K, R\u00fcb U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson\u2019s disease. Neurobiol Aging 24:197\u2013211. https:\/\/doi.org\/10.1016\/s0197-4580(02)00065-9","journal-title":"Neurobiol Aging"},{"key":"1575_CR7","doi-asserted-by":"publisher","first-page":"R139","DOI":"10.1093\/hmg\/ddx273","volume":"26","author":"V Carelli","year":"2017","unstructured":"Carelli V, La Morgia C, Ross-Cisneros FN, Sadun AA (2017) Optic neuropathies: the tip of the neurodegeneration iceberg. Hum Mol Genet 26:R139\u2013R150. https:\/\/doi.org\/10.1093\/hmg\/ddx273","journal-title":"Hum Mol Genet"},{"key":"1575_CR8","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1186\/s12886-021-02196-8","volume":"21","author":"P-YJ Chen","year":"2021","unstructured":"Chen P-YJ, Wan L, Lai J-N, Chen CS, Chen JJ-Y, Yen WM, Chiu L-T, Hu K-C, Tien P-T, Lin H-J (2021) Increased risk of Parkinson\u2019s disease among patients with age-related macular degeneration. BMC Ophthalmol 21:426. https:\/\/doi.org\/10.1186\/s12886-021-02196-8","journal-title":"BMC Ophthalmol"},{"key":"1575_CR9","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.ajo.2019.11.001","volume":"210","author":"S Choi","year":"2020","unstructured":"Choi S, Jahng WJ, Park SM, Jee D (2020) Association of age-related macular degeneration on Alzheimer or Parkinson disease: a retrospective cohort study. Am J Ophthalmol 210:41\u201347. https:\/\/doi.org\/10.1016\/j.ajo.2019.11.001","journal-title":"Am J Ophthalmol"},{"key":"1575_CR10","doi-asserted-by":"publisher","first-page":"139","DOI":"10.14802\/jmd.19046","volume":"12","author":"HK Chung","year":"2019","unstructured":"Chung HK, Ho HA, P\u00e9rez-Acu\u00f1a D, Lee SJ (2019) Modeling \u03b1-synuclein propagation with preformed fibril injections. J Mov Disord 12:139\u2013151. https:\/\/doi.org\/10.14802\/jmd.19046","journal-title":"J Mov Disord"},{"key":"1575_CR11","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1016\/s1474-4422(06)70471-9","volume":"5","author":"LM de Lau","year":"2006","unstructured":"de Lau LM, Breteler MM (2006) Epidemiology of Parkinson\u2019s disease. Lancet Neurol 5:525\u2013535. https:\/\/doi.org\/10.1016\/s1474-4422(06)70471-9","journal-title":"Lancet Neurol"},{"key":"1575_CR12","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1186\/s12974-019-1636-8","volume":"16","author":"RH Earls","year":"2019","unstructured":"Earls RH, Menees KB, Chung J, Barber J, Gutekunst C-A, Hazim MG, Lee J-K (2019) Intrastriatal injection of preformed alpha-synuclein fibrils alters central and peripheral immune cell profiles in non-transgenic mice. J Neuroinflammat 16:250. https:\/\/doi.org\/10.1186\/s12974-019-1636-8","journal-title":"J Neuroinflammat"},{"key":"1575_CR13","first-page":"325","volume-title":"Handbook of clinical neurology","author":"DA Fox","year":"2015","unstructured":"Fox DA (2015) Chapter 18 - Retinal and visual system: occupational and environmental toxicology. In: Lotti M, Bleecker ML (eds) Handbook of clinical neurology. Elsevier, Amsterdam, pp 325\u2013340"},{"key":"1575_CR14","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1038\/s41380-021-01296-7","volume":"27","author":"Y-J Guo","year":"2022","unstructured":"Guo Y-J, Xiong H, Chen K, Zou J-J, Lei P (2022) Brain regions susceptible to alpha-synuclein spreading. Mol Psychiat 27:758\u2013770. https:\/\/doi.org\/10.1038\/s41380-021-01296-7","journal-title":"Mol Psychiat"},{"key":"1575_CR15","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1038\/s41593-019-0457-5","volume":"22","author":"MX Henderson","year":"2019","unstructured":"Henderson MX, Cornblath EJ, Darwich A, Zhang B, Brown H, Gathagan RJ, Sandler RM, Bassett DS, Trojanowski JQ, Lee VMY (2019) Spread of alpha-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis. Nat Neurosci 22:1248\u20131257. https:\/\/doi.org\/10.1038\/s41593-019-0457-5","journal-title":"Nat Neurosci"},{"key":"1575_CR16","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1038\/s41586-019-1769-z","volume":"575","author":"C Ising","year":"2019","unstructured":"Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, Schwartz S, Albasset S, McManus RM, Tejera D et al (2019) NLRP3 inflammasome activation drives tau pathology. Nature 575:669\u2013673. https:\/\/doi.org\/10.1038\/s41586-019-1769-z","journal-title":"Nature"},{"key":"1575_CR17","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1167\/iovs.61.6.12","volume":"61","author":"K Kaehler","year":"2020","unstructured":"Kaehler K, Seitter H, Sandbichler AM, Tschugg B, Obermair GJ, Stefanova N, Koschak A (2020) Assessment of the retina of Plp-\u03b1-Syn mice as a model for studying synuclein-dependent diseases. Invest Ophthalmol Vis Sci 61:12\u201312. https:\/\/doi.org\/10.1167\/iovs.61.6.12","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"1575_CR18","doi-asserted-by":"publisher","first-page":"2148","DOI":"10.1038\/s12276-022-00895-w","volume":"54","author":"T-K Kim","year":"2022","unstructured":"Kim T-K, Bae E-J, Jung BC, Choi M, Shin SJ, Park SJ, Kim JT, Jung MK, Ulusoy A, Song M-Y et al (2022) Inflammation promotes synucleinopathy propagation. Exp Mol Med 54:2148\u20132161. https:\/\/doi.org\/10.1038\/s12276-022-00895-w","journal-title":"Exp Mol Med"},{"key":"1575_CR19","doi-asserted-by":"publisher","first-page":"4115","DOI":"10.1167\/iovs.17-23230","volume":"59","author":"WR Kwapong","year":"2018","unstructured":"Kwapong WR, Ye H, Peng C, Zhuang X, Wang J, Shen M, Lu F (2018) Retinal microvascular impairment in the early stages of parkinson\u2019s disease. Invest Ophthalmol Vis Sci 59:4115\u20134122. https:\/\/doi.org\/10.1167\/iovs.17-23230","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"1575_CR20","doi-asserted-by":"publisher","first-page":"710","DOI":"10.3389\/fneur.2017.00710","volume":"8","author":"C La Morgia","year":"2017","unstructured":"La Morgia C, Di Vito L, Carelli V, Carbonelli M (2017) Patterns of retinal ganglion cell damage in neurodegenerative disorders: parvocellular vs magnocellular degeneration in optical coherence tomography studies. Front Neurol 8:710","journal-title":"Front Neurol"},{"key":"1575_CR21","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1002\/mds.27914","volume":"35","author":"J-Y Lee","year":"2020","unstructured":"Lee J-Y, Ahn J, Oh S, Shin JY, Kim YK, Nam H, Jeon B (2020) Retina thickness as a marker of neurodegeneration in prodromal Lewy body disease. Mov Disord 35:349\u2013354. https:\/\/doi.org\/10.1002\/mds.27914","journal-title":"Mov Disord"},{"key":"1575_CR22","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1002\/ana.25972","volume":"89","author":"J-Y Lee","year":"2021","unstructured":"Lee J-Y, Ahn J, Shin JY, Jeon B (2021) Parafoveal change and dopamine loss in the retina with Parkinson\u2019s disease. Ann Neurol 89:421\u2013422. https:\/\/doi.org\/10.1002\/ana.25972","journal-title":"Ann Neurol"},{"key":"1575_CR23","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41582-022-00618-9","volume":"18","author":"J-Y Lee","year":"2022","unstructured":"Lee J-Y, Martin-Bastida A, Murueta-Goyena A, Gabilondo I, Cuenca N, Piccini P, Jeon B (2022) Multimodal brain and retinal imaging of dopaminergic degeneration in Parkinson disease. Nat Rev Neurol 18:203\u2013220. https:\/\/doi.org\/10.1038\/s41582-022-00618-9","journal-title":"Nat Rev Neurol"},{"key":"1575_CR24","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1038\/nrneurol.2010.145","volume":"6","author":"S-J Lee","year":"2010","unstructured":"Lee S-J, Desplats P, Sigurdson C, Tsigelny I, Masliah E (2010) Cell-to-cell transmission of non-prion protein aggregates. Nat Rev Neurol 6:702\u2013706. https:\/\/doi.org\/10.1038\/nrneurol.2010.145","journal-title":"Nat Rev Neurol"},{"key":"1575_CR25","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1097\/NEN.0b013e31820376cc","volume":"70","author":"F Leger","year":"2011","unstructured":"Leger F, Fernagut PO, Canron MH, Leoni S, Vital C, Tison F, Bezard E, Vital A (2011) Protein aggregation in the aging retina. J Neuropathol Exp Neurol 70:63\u201368. https:\/\/doi.org\/10.1097\/NEN.0b013e31820376cc","journal-title":"J Neuropathol Exp Neurol"},{"key":"1575_CR26","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/nature05453","volume":"445","author":"ES Lein","year":"2007","unstructured":"Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, Boe AF, Boguski MS, Brockway KS, Byrnes EJ et al (2007) Genome-wide atlas of gene expression in the adult mouse brain. Nature 445:168\u2013176. https:\/\/doi.org\/10.1038\/nature05453","journal-title":"Nature"},{"key":"1575_CR27","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.pneurobio.2018.06.010","volume":"169","author":"S Lim","year":"2018","unstructured":"Lim S, Kim H-J, Kim D-K, Lee S-J (2018) Non-cell-autonomous actions of \u03b1-synuclein: Implications in glial synucleinopathies. Prog Neurobiol 169:158\u2013171. https:\/\/doi.org\/10.1016\/j.pneurobio.2018.06.010","journal-title":"Prog Neurobiol"},{"key":"1575_CR28","doi-asserted-by":"publisher","first-page":"3373","DOI":"10.1016\/j.celrep.2016.08.053","volume":"16","author":"KC Luk","year":"2016","unstructured":"Luk KC, Covell DJ, Kehm VM, Zhang B, Song IY, Byrne MD, Pitkin RM, Decker SC, Trojanowski JQ, Lee VMY (2016) Molecular and biological compatibility with host alpha-synuclein influences fibril pathogenicity. Cell Rep 16:3373\u20133387. https:\/\/doi.org\/10.1016\/j.celrep.2016.08.053","journal-title":"Cell Rep"},{"key":"1575_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.nbd.2018.09.013","volume":"121","author":"N Mammadova","year":"2019","unstructured":"Mammadova N, Summers CM, Kokemuller RD, He Q, Ding S, Baron T, Yu C, Valentine RJ, Sakaguchi DS, Kanthasamy AG et al (2019) Accelerated accumulation of retinal \u03b1-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson\u2019s disease. Neurobiol Dis 121:1\u201316. https:\/\/doi.org\/10.1016\/j.nbd.2018.09.013","journal-title":"Neurobiol Dis"},{"key":"1575_CR30","doi-asserted-by":"publisher","first-page":"9619","DOI":"10.1038\/s41598-020-66497-6","volume":"10","author":"E Marrocco","year":"2020","unstructured":"Marrocco E, Indrieri A, Esposito F, Tarallo V, Carboncino A, Alvino FG, De Falco S, Franco B, De Risi M, De Leonibus E (2020) \u03b1-synuclein overexpression in the retina leads to vision impairment and degeneration of dopaminergic amacrine cells. Sci Rep 10:9619. https:\/\/doi.org\/10.1038\/s41598-020-66497-6","journal-title":"Sci Rep"},{"key":"1575_CR31","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13024-022-00528-w","volume":"17","author":"T McLaughlin","year":"2022","unstructured":"McLaughlin T, Medina A, Perkins J, Yera M, Wang JJ, Zhang SX (2022) Cellular stress signaling and the unfolded protein response in retinal degeneration: mechanisms and therapeutic implications. Mol Neurodegener 17:25. https:\/\/doi.org\/10.1186\/s13024-022-00528-w","journal-title":"Mol Neurodegener"},{"key":"1575_CR32","doi-asserted-by":"publisher","first-page":"104623","DOI":"10.1016\/j.nbd.2019.104623","volume":"134","author":"C Mezias","year":"2020","unstructured":"Mezias C, Rey N, Brundin P, Raj A (2020) Neural connectivity predicts spreading of alpha-synuclein pathology in fibril-injected mouse models: Involvement of retrograde and anterograde axonal propagation. Neurobiol Dis 134:104623. https:\/\/doi.org\/10.1016\/j.nbd.2019.104623","journal-title":"Neurobiol Dis"},{"key":"1575_CR33","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/978-1-4614-0631-0_12","volume-title":"Retinal degenerative diseases","author":"SK Mitter","year":"2012","unstructured":"Mitter SK, Rao HV, Qi X, Cai J, Sugrue A, Dunn WA, Grant MB, Boulton ME (2012) Autophagy in the retina: a potential role in age-related macular degeneration. In: LaVail MM, Ash JD, Anderson RE, Hollyfield JG, Grimm C (eds) Retinal degenerative diseases. Springer, Berlin, pp 83\u201390"},{"key":"1575_CR34","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.molmed.2012.03.005","volume":"18","author":"KL Moreau","year":"2012","unstructured":"Moreau KL, King JA (2012) Protein misfolding and aggregation in cataract disease and prospects for prevention. Trends Mol Med 18:273\u2013282. https:\/\/doi.org\/10.1016\/j.molmed.2012.03.005","journal-title":"Trends Mol Med"},{"key":"1575_CR35","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1002\/mds.27392","volume":"33","author":"I Ortu\u00f1o-Lizar\u00e1n","year":"2018","unstructured":"Ortu\u00f1o-Lizar\u00e1n I, Beach TG, Serrano GE, Walker DG, Adler CH, Cuenca N (2018) Phosphorylated \u03b1-synuclein in the retina is a biomarker of Parkinson\u2019s disease pathology severity. Mov Disord 33:1315\u20131324. https:\/\/doi.org\/10.1002\/mds.27392","journal-title":"Mov Disord"},{"key":"1575_CR36","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1002\/ana.25897","volume":"88","author":"I Ortu\u00f1o-Lizar\u00e1n","year":"2020","unstructured":"Ortu\u00f1o-Lizar\u00e1n I, S\u00e1nchez-S\u00e1ez X, Lax P, Serrano GE, Beach TG, Adler CH, Cuenca N (2020) Dopaminergic retinal cell loss and visual dysfunction in Parkinson disease. Ann Neurol 88:893\u2013906. https:\/\/doi.org\/10.1002\/ana.25897","journal-title":"Ann Neurol"},{"key":"1575_CR37","doi-asserted-by":"publisher","DOI":"10.3791\/59758","author":"JR Patterson","year":"2019","unstructured":"Patterson JR, Polinski NK, Duffy MF, Kemp CJ, Luk KC, Volpicelli-Daley LA, Kanaan NM, Sortwell CE (2019) Generation of alpha-synuclein preformed fibrils from monomers and use in vivo. J Vis Exp. https:\/\/doi.org\/10.3791\/59758","journal-title":"J Vis Exp"},{"key":"1575_CR38","doi-asserted-by":"publisher","first-page":"4420","DOI":"10.1167\/iovs.16-20020","volume":"57","author":"A Pilat","year":"2016","unstructured":"Pilat A, McLean RJ, Proudlock FA, Maconachie GDE, Sheth V, Rajabally YA, Gottlob I (2016) In vivo morphology of the optic nerve and retina in patients with Parkinson\u2019s disease. Invest Ophthalmol Vis Sci 57:4420\u20134427. https:\/\/doi.org\/10.1167\/iovs.16-20020","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"1575_CR39","doi-asserted-by":"publisher","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","volume":"3","author":"W Poewe","year":"2017","unstructured":"Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag A-E, Lang AE (2017) Parkinson disease. Nat Rev Dis Primers 3:17013. https:\/\/doi.org\/10.1038\/nrdp.2017.13","journal-title":"Nat Rev Dis Primers"},{"key":"1575_CR40","doi-asserted-by":"publisher","first-page":"303","DOI":"10.3233\/jpd-171248","volume":"8","author":"NK Polinski","year":"2018","unstructured":"Polinski NK, Volpicelli-Daley LA, Sortwell CE, Luk KC, Cremades N, Gottler LM, Froula J, Duffy MF, Lee VMY, Martinez TN et al (2018) Best practices for generating and using alpha-synuclein pre-formed fibrils to model Parkinson\u2019s disease in rodents. J Parkinsons Dis 8:303\u2013322. https:\/\/doi.org\/10.3233\/jpd-171248","journal-title":"J Parkinsons Dis"},{"key":"1575_CR41","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s13041-017-0340-9","volume":"10","author":"L Puspita","year":"2017","unstructured":"Puspita L, Chung SY, Shim J-w (2017) Oxidative stress and cellular pathologies in Parkinson\u2019s disease. Mol Brain 10:53. https:\/\/doi.org\/10.1186\/s13041-017-0340-9","journal-title":"Mol Brain"},{"key":"1575_CR42","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1093\/brain\/awab440","volume":"145","author":"S Rahayel","year":"2022","unstructured":"Rahayel S, Mi\u0161i\u0107 B, Zheng Y-Q, Liu Z-Q, Abdelgawad A, Abbasi N, Caputo A, Zhang B, Lo A, Kehm V et al (2022) Differentially targeted seeding reveals unique pathological alpha-synuclein propagation patterns. Brain 145:1743\u20131756. https:\/\/doi.org\/10.1093\/brain\/awab440","journal-title":"Brain"},{"key":"1575_CR43","doi-asserted-by":"publisher","first-page":"533375","DOI":"10.3389\/fneur.2020.533375","volume":"11","author":"C Rascun\u00e0","year":"2020","unstructured":"Rascun\u00e0 C, Russo A, Terravecchia C, Castellino N, Avitabile T, Bonfiglio V, Fallico M, Chisari CG, Cicero CE, Grillo M et al (2020) Retinal thickness and microvascular pattern in early Parkinson\u2019s disease. Front Neurol 11:533375","journal-title":"Front Neurol"},{"key":"1575_CR44","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2014.00159","author":"A Recasens","year":"2014","unstructured":"Recasens A, Dehay B (2014) Alpha-synuclein spreading in Parkinson\u2019s disease. Front Neuroanat. https:\/\/doi.org\/10.3389\/fnana.2014.00159","journal-title":"Front Neuroanat"},{"key":"1575_CR45","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1007\/s00401-013-1160-3","volume":"126","author":"NL Rey","year":"2013","unstructured":"Rey NL, Petit GH, Bousset L, Melki R, Brundin P (2013) Transfer of human \u03b1-synuclein from the olfactory bulb to interconnected brain regions in mice. Acta Neuropathol 126:555\u2013573. https:\/\/doi.org\/10.1007\/s00401-013-1160-3","journal-title":"Acta Neuropathol"},{"key":"1575_CR46","first-page":"4012","volume":"60","author":"X S\u00e1nchez-S\u00e1ez","year":"2019","unstructured":"S\u00e1nchez-S\u00e1ez X, Ortu\u00f1o Lizar\u00e1n I, Beach TG, Serrano GE, Adler CH, Cuenca N (2019) Retinal Ganglion cell degeneration in patients with Parkinson disease induce optic nerve bundles remodelling and microglia activation. Invest Ophthalmol Vis Sci 60:4012\u20134012","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"1575_CR47","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1001\/jamaneurol.2017.4243","volume":"75","author":"R Savica","year":"2018","unstructured":"Savica R, Boeve BF, Mielke MM (2018) When do \u03b1-synucleinopathies start? An epidemiological timeline: a review. JAMA Neurol 75:503\u2013509. https:\/\/doi.org\/10.1001\/jamaneurol.2017.4243","journal-title":"JAMA Neurol"},{"key":"1575_CR48","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.survophthal.2021.06.001","volume":"67","author":"S Sharma","year":"2022","unstructured":"Sharma S, Chitranshi N, Wall RV, Basavarajappa D, Gupta V, Mirzaei M, Graham SL, Klistorner A, You Y (2022) Trans-synaptic degeneration in the visual pathway: neural connectivity, pathophysiology, and clinical implications in neurodegenerative disorders. Surv Ophthalmol 67:411\u2013426. https:\/\/doi.org\/10.1016\/j.survophthal.2021.06.001","journal-title":"Surv Ophthalmol"},{"key":"1575_CR49","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.csbj.2021.12.017","volume":"20","author":"JC Shillcock","year":"2022","unstructured":"Shillcock JC, Hastings J, Riguet N, Lashuel HA (2022) Non-monotonic fibril surface occlusion by GFP tags from coarse-grained molecular simulations. Comput Struct Biotechnol J 20:309\u2013321. https:\/\/doi.org\/10.1016\/j.csbj.2021.12.017","journal-title":"Comput Struct Biotechnol J"},{"key":"1575_CR50","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.bbadis.2004.08.004","volume":"1739","author":"M Stefani","year":"2004","unstructured":"Stefani M (2004) Protein misfolding and aggregation: new examples in medicine and biology of the dark side of the protein world. Biochimica et Biophysica Acta BBA Mol Basis Disease 1739:5\u201325. https:\/\/doi.org\/10.1016\/j.bbadis.2004.08.004","journal-title":"Biochimica et Biophysica Acta BBA Mol Basis Disease"},{"key":"1575_CR51","doi-asserted-by":"publisher","first-page":"11832","DOI":"10.1038\/s41598-019-48388-7","volume":"9","author":"MS Sung","year":"2019","unstructured":"Sung MS, Choi S-M, Kim J, Ha JY, Kim B-C, Heo H, Park SW (2019) Inner retinal thinning as a biomarker for cognitive impairment in de novo Parkinson\u2019s disease. Sci Rep 9:11832. https:\/\/doi.org\/10.1038\/s41598-019-48388-7","journal-title":"Sci Rep"},{"key":"1575_CR52","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a007492","author":"R Tzekov","year":"2011","unstructured":"Tzekov R, Stein L, Kaushal S (2011) Protein misfolding and retinal degeneration. Csh Perspect Biol. https:\/\/doi.org\/10.1101\/cshperspect.a007492","journal-title":"Csh Perspect Biol"},{"key":"1575_CR53","doi-asserted-by":"crossref","unstructured":"Veys L, Devroye J, Lefevere E, Cools L, Vandenabeele M, De Groef L (2021) Characterizing the retinal phenotype of the Thy1-h[A30P]\u03b1-syn mouse model of Parkinson\u2019s disease. Front Neurosci 15","DOI":"10.3389\/fnins.2021.726476"},{"key":"1575_CR54","doi-asserted-by":"publisher","first-page":"614587","DOI":"10.3389\/fnagi.2020.614587","volume":"12","author":"L Veys","year":"2020","unstructured":"Veys L, Van Houcke J, Aerts J, Van Pottelberge S, Mahieu M, Coens A, Melki R, Moechars D, De Muynck L, De Groef L (2020) Absence of uptake and prion-like spreading of alpha-synuclein and tau after intravitreal injection of preformed fibrils. Front Aging Neurosci 12:614587. https:\/\/doi.org\/10.3389\/fnagi.2020.614587","journal-title":"Front Aging Neurosci"},{"key":"1575_CR55","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/2051-5960-1-2","volume":"1","author":"NP Visanji","year":"2013","unstructured":"Visanji NP, Brooks PL, Hazrati L-N, Lang AE (2013) The prion hypothesis in Parkinson\u2019s disease: braak to the future. Acta Neuropathol Commun 1:2. https:\/\/doi.org\/10.1186\/2051-5960-1-2","journal-title":"Acta Neuropathol Commun"},{"key":"1575_CR56","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1038\/nprot.2014.143","volume":"9","author":"LA Volpicelli-Daley","year":"2014","unstructured":"Volpicelli-Daley LA, Luk KC, Lee VM (2014) Addition of exogenous \u03b1-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous \u03b1-synuclein to Lewy body and Lewy neurite-like aggregates. Nat Protoc 9:2135\u20132146. https:\/\/doi.org\/10.1038\/nprot.2014.143","journal-title":"Nat Protoc"},{"key":"1575_CR57","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.bpj.2018.12.010","volume":"116","author":"J W\u00e4gele","year":"2019","unstructured":"W\u00e4gele J, De Sio S, Voigt B, Balbach J, Ott M (2019) How fluorescent tags modify oligomer size distributions of the Alzheimer peptide. Biophys J 116:227\u2013238. https:\/\/doi.org\/10.1016\/j.bpj.2018.12.010","journal-title":"Biophys J"},{"key":"1575_CR58","doi-asserted-by":"publisher","first-page":"5177","DOI":"10.1523\/JNEUROSCI.0471-20.2020","volume":"40","author":"Y Wenjun","year":"2020","unstructured":"Wenjun Y, Mallory AL, Nicholas MT, Irene EW, Inbal B, Joshua RS (2020) Mouse retinal cell atlas: molecular identification of over sixty amacrine cell types. J Neurosci 40:5177. https:\/\/doi.org\/10.1523\/JNEUROSCI.0471-20.2020","journal-title":"J Neurosci"},{"key":"1575_CR59","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1080\/15548627.2018.1463121","volume":"14","author":"J Yao","year":"2018","unstructured":"Yao J, Qiu Y, Frontera E, Jia L, Khan NW, Klionsky DJ, Ferguson TA, Thompson DA, Zacks DN (2018) Inhibiting autophagy reduces retinal degeneration caused by protein misfolding. Autophagy 14:1226\u20131238. https:\/\/doi.org\/10.1080\/15548627.2018.1463121","journal-title":"Autophagy"},{"key":"1575_CR60","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.3389\/fnins.2021.799526","volume":"15","author":"Y Zhang","year":"2022","unstructured":"Zhang Y, Zhang X, Yue Y, Tian T (2022) Retinal degeneration: a window to understand the origin and progression of Parkinson\u2019s disease? Front Neurosci 15:1803","journal-title":"Front Neurosci"},{"key":"1575_CR61","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1007\/s12264-019-00445-x","volume":"36","author":"Z Zhang","year":"2020","unstructured":"Zhang Z, Liu W, Huang Y, Luo L, Cai X, Liu Y, Ai L, Yan J, Lin S, Ye J (2020) NLRP3 deficiency attenuates secondary degeneration of visual cortical neurons following optic nerve injury. Neurosci Bull 36:277\u2013288. https:\/\/doi.org\/10.1007\/s12264-019-00445-x","journal-title":"Neurosci Bull"},{"key":"1575_CR62","doi-asserted-by":"publisher","first-page":"168","DOI":"10.5114\/fn.2017.68584","volume":"55","author":"M \u017divkovi\u0107","year":"2017","unstructured":"\u017divkovi\u0107 M, Dayanir V, Stamenovi\u0107 J, Ljubisavljevi\u0107 S, Pra\u017ei\u0107 A, Zlatanovi\u0107 M, Zlatanovi\u0107 G, Jak\u0161i\u0107 V, Radenkovi\u0107 M, Jovanovi\u0107 S (2017) Retinal ganglion cell\/inner plexiform layer thickness in patients with Parkinson\u2019s disease. Folia Neuropathol 55:168\u2013173. https:\/\/doi.org\/10.5114\/fn.2017.68584","journal-title":"Folia Neuropathol"}],"updated-by":[{"DOI":"10.1186\/s40478-024-01816-w","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T00:00:00Z","timestamp":1719878400000}}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-023-01575-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-023-01575-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-023-01575-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T06:08:07Z","timestamp":1719986887000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-023-01575-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,20]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["1575"],"URL":"https:\/\/doi.org\/10.1186\/s40478-023-01575-0","relation":{"correction":[{"id-type":"doi","id":"10.1186\/s40478-024-01816-w","asserted-by":"object"}]},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,20]]},"assertion":[{"value":"25 April 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 April 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 May 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 July 2024","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1186\/s40478-024-01816-w","URL":"https:\/\/doi.org\/10.1186\/s40478-024-01816-w","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All mouse experiments were performed in accordance with the requirements of the Seoul National University Institutional Animal Care and Use Committee (IACUC) (SNU-200424\u20133-3).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"SJL is co-founder and CEO of Neuramedy Co. Ltd. All other authors declare no competing financial interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"83"}}