{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T23:27:52Z","timestamp":1786577272573,"version":"build-2736575974"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":93,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100012363","name":"Saudi Arabia Cultural Bureau in London","doi-asserted-by":"publisher","award":["G102704"],"award-info":[{"award-number":["G102704"]}],"id":[{"id":"10.13039\/100012363","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Elite Scholarship Program, Ministry of Education"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder characterised by the misfolding and accumulation of \u03b1-synuclein (\u03b1-syn) into pathological aggregates known as Lewy bodies. PD remains incurable, partly due to limited physiologically relevant models that recapitulate human pathology to enable therapeutic development. We developed a novel in vitro PD dementia model using fetal human cortical neurons seeded with \u03b1-syn preformed fibrils (PFFs). This model successfully replicates key PD features, including \u03b1-syn aggregation and mitochondrial gene dysregulation. Importantly, RNA sequencing revealed significant transcriptomic concordance between our model and PD postmortem tissue, particularly in the downregulation of mitochondrial genes linked to oxidative phosphorylation. We then evaluated two peptide inhibitors, \u03b2-syn36D (B36D) and S62. Both peptides demonstrated effective disaggregation of \u03b1-syn fibrils, with B36D showing particular promise by reversing PFF-induced functional and transcriptional changes to baseline levels. This human-relevant model captures essential pathological and transcriptomic disease hallmarks as well as demonstrating utility for therapeutic screening of drugs that block \u03b1-syn aggregation.<\/jats:p>","DOI":"10.1038\/s42003-026-10134-x","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T16:45:10Z","timestamp":1778604310000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Early \u03b1-synuclein\u2013mediated mitochondrial dysfunction in a human cell model of Parkinson\u2019s disease dementia"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1380-9935","authenticated-orcid":false,"given":"Maha S.","family":"Alfaidi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9a M. D.","family":"Wenger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1558-8372","authenticated-orcid":false,"given":"Korn\u00e9lia","family":"Szeb\u00e9nyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas B.","family":"Stoker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1002-8418","authenticated-orcid":false,"given":"Xiaoling","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaline V.","family":"Fazal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Sebestikova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Jassim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7539-9472","authenticated-orcid":false,"given":"Richard J.","family":"Gilbertson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2524-3055","authenticated-orcid":false,"given":"Raquel","family":"Garza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Jakobsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Grazia","family":"Spillantini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8843-7730","authenticated-orcid":false,"given":"Roger A.","family":"Barker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0273-1320","authenticated-orcid":false,"given":"Wei-Li","family":"Kuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"10134_CR1","unstructured":"Lewy, F. H. Paralysis agitans. I. Pathologische anatomie. Handbuch der Neurologie 3, 920\u2013958 (1912)."},{"key":"10134_CR2","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1136\/jnnp.2011.240366","volume":"82","author":"JR Evans","year":"2011","unstructured":"Evans, J. R. et al. The natural history of treated Parkinson\u2019s disease in an incident, community based cohort. J. Neurol. Neurosurg. Psychiatry 82, 1112\u20131118 (2011).","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"10134_CR3","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1002\/mds.21956","volume":"23","author":"MA Hely","year":"2008","unstructured":"Hely, M. A., Reid, W. G., Adena, M. A., Halliday, G. M. & Morris, J. G. L. The Sydney multicenter study of Parkinson\u2019s disease: the inevitability of dementia at 20 years. Mov. Disord. 23, 837\u2013844 (2008).","journal-title":"Mov. Disord."},{"key":"10134_CR4","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1126\/science.276.5321.2045","volume":"276","author":"MH Polymeropoulos","year":"1997","unstructured":"Polymeropoulos, M. H. et al. Mutation in the \u03b1-synuclein gene identified in families with Parkinson\u2019s disease. Science 276, 2045\u20132047 (1997).","journal-title":"Science"},{"key":"10134_CR5","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1002\/mds.25421","volume":"28","author":"S Appel-Cresswell","year":"2013","unstructured":"Appel-Cresswell, S. et al. Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson\u2019s disease. Mov. Disord. 28, 811\u2013813 (2013).","journal-title":"Mov. Disord."},{"key":"10134_CR6","unstructured":"Kruger, R. Ala30Pro mutation in the gene encoding a-synuclein in Parkinson\u2019s disease. http:\/\/www.nature.com\/naturegenetics (2020)."},{"key":"10134_CR7","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1007\/s00401-023-02550-8","volume":"145","author":"Y Yang","year":"2023","unstructured":"Yang, Y. et al. New SNCA mutation and structures of \u03b1-synuclein filaments from juvenile-onset synucleinopathy. Acta Neuropathol. 145, 561\u2013572 (2023).","journal-title":"Acta Neuropathol."},{"key":"10134_CR8","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/42166","volume":"388","author":"MG Spillantini","year":"1997","unstructured":"Spillantini, M. G. et al. \u03b1-synuclein in Lewy bodies. Nature 388, 839\u2013840 (1997).","journal-title":"Nature"},{"key":"10134_CR9","doi-asserted-by":"publisher","first-page":"29739","DOI":"10.1074\/jbc.M600933200","volume":"281","author":"JP Anderson","year":"2006","unstructured":"Anderson, J. P. et al. Phosphorylation of Ser-129 is the dominant pathological modification of \u03b1-synuclein in familial and sporadic Lewy body disease. J. Biol. Chem. 281, 29739\u201329752 (2006).","journal-title":"J. Biol. Chem."},{"key":"10134_CR10","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1002\/ana.23746","volume":"73","author":"LV Kalia","year":"2013","unstructured":"Kalia, L. V., Kalia, S. K., McLean, P. J., Lozano, A. M. & Lang, A. E. \u03b1-synuclein oligomers and clinical implications for Parkinson disease. Ann. Neurol. 73, 155\u2013169 (2013).","journal-title":"Ann. Neurol."},{"key":"10134_CR11","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1126\/science.1227157","volume":"338","author":"KC Luk","year":"2012","unstructured":"Luk, K. C. et al. Pathological \u03b1-synuclein transmission initiates Parkinson-like neurodegeneration in non-transgenic mice. Science 338, 949 (2012).","journal-title":"Science"},{"key":"10134_CR12","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.neuron.2011.08.033","volume":"72","author":"LA Volpicelli-Daley","year":"2011","unstructured":"Volpicelli-Daley, L. A. et al. Exogenous \u03b1-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57\u201371 (2011).","journal-title":"Neuron"},{"key":"10134_CR13","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1038\/s41380-019-0608-9","volume":"26","author":"W-L Kuan","year":"2021","unstructured":"Kuan, W.-L. et al. Systemic \u03b1-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson\u2019s disease. Mol. Psychiatry 26, 556\u2013567 (2021).","journal-title":"Mol. Psychiatry"},{"key":"10134_CR14","doi-asserted-by":"publisher","unstructured":"Kuan, W. L. et al. Selective neurodegeneration generated by intravenous \u03b1-synuclein pre-formed fibril administration is not associated with endogenous \u03b1-synuclein levels in the rat brain. Brain Pathol. 33 https:\/\/doi.org\/10.1111\/bpa.13128 (2023).","DOI":"10.1111\/bpa.13128"},{"key":"10134_CR15","doi-asserted-by":"publisher","unstructured":"Luk, K. C. et al. Pathological \u03b1-synuclein transmission initiates Parkinson-like neurodegeneration in non-transgenic mice. https:\/\/doi.org\/10.1126\/science.1227157 (2012),","DOI":"10.1126\/science.1227157"},{"key":"10134_CR16","doi-asserted-by":"publisher","unstructured":"Tanri\u00f6ver, G. et al. Prominent microglial inclusions in transgenic mouse models of \u03b1-synucleinopathy that are distinct from neuronal lesions. Acta Neuropathol. Commun. 8 https:\/\/doi.org\/10.1186\/s40478-020-00993-8 (2020).","DOI":"10.1186\/s40478-020-00993-8"},{"key":"10134_CR17","doi-asserted-by":"publisher","unstructured":"Barbuti, P. A. et al. The role of alpha-synuclein in synucleinopathy: impact on lipid regulation at mitochondria\u2013ER membranes. NPJ Parkinsons Dis. 11 https:\/\/doi.org\/10.1038\/s41531-025-00960-x (2025).","DOI":"10.1038\/s41531-025-00960-x"},{"key":"10134_CR18","doi-asserted-by":"publisher","unstructured":"Van Dyck, C. H. et al. Lecanemab in early Alzheimer\u2019s disease. Krause und Pachernegg GmbH. https:\/\/doi.org\/10.1056\/nejmoa2212948 (2021).","DOI":"10.1056\/nejmoa2212948"},{"key":"10134_CR19","doi-asserted-by":"publisher","unstructured":"Shaltiel-Karyo, R. et al. Inhibiting \u03b1-synuclein oligomerization by stable cell-penetrating \u03b2-synuclein fragments recovers phenotype of parkinson\u2019s disease model flies. PLoS ONE 5 https:\/\/doi.org\/10.1371\/journal.pone.0013863 (2010).","DOI":"10.1371\/journal.pone.0013863"},{"key":"10134_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/eLife.46775","volume":"9","author":"S Sangwan","year":"2020","unstructured":"Sangwan, S. et al. Inhibition of synucleinopathic seeding by rationally designed inhibitors. Elife 9, 1\u201319 (2020).","journal-title":"Elife"},{"key":"10134_CR21","doi-asserted-by":"publisher","unstructured":"Kuan, W.-L. et al. Systemic \u03b1-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson\u2019s disease. Mol. Psychiatry https:\/\/doi.org\/10.1038\/s41380-019-0608-9 (2019).","DOI":"10.1038\/s41380-019-0608-9"},{"key":"10134_CR22","doi-asserted-by":"publisher","unstructured":"Jassim, A. et al. Natural language processing charts transcriptome evolution to design combination cancer therapies. https:\/\/doi.org\/10.1101\/2024.04.09.585681 (2024).","DOI":"10.1101\/2024.04.09.585681"},{"key":"10134_CR23","doi-asserted-by":"publisher","unstructured":"Paxinou, E. et al. Induction of alpha-synuclein aggregation by intracellular nitrative insult. Journal of Neuroscience, 21, 8053\u20138061. https:\/\/doi.org\/10.1523\/JNEUROSCI.21-20-08053.2001 (2001).","DOI":"10.1523\/JNEUROSCI.21-20-08053.2001"},{"key":"10134_CR24","doi-asserted-by":"crossref","unstructured":"Luk, K. C. et al. Exogenous \u03b1-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc. Natl. Acad. Sci. USA. 106, 20051\u201320056 (2009).","DOI":"10.1073\/pnas.0908005106"},{"key":"10134_CR25","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1038\/s41593-019-0457-5","volume":"22","author":"MX Henderson","year":"2019","unstructured":"Henderson, M. X. et al. Spread of \u03b1-synuclein pathology through the brain connectome is modulated by selective vulnerability and predicted by network analysis. Nat. Neurosci. 22, 1248\u20131257 (2019).","journal-title":"Nat. Neurosci."},{"key":"10134_CR26","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1016\/j.stemcr.2018.12.007","volume":"12","author":"S Gribaudo","year":"2019","unstructured":"Gribaudo, S. et al. Propagation of \u03b1-synuclein strains within human reconstructed neuronal network. Stem Cell Rep. 12, 230\u2013244 (2019).","journal-title":"Stem Cell Rep."},{"key":"10134_CR27","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1111\/ejn.14286","volume":"49","author":"Y Chen","year":"2019","unstructured":"Chen, Y. et al. Engineering synucleinopathy-resistant human dopaminergic neurons by CRISPR-mediated deletion of the SNCA gene. Eur. J. Neurosci. 49, 510\u2013524 (2019).","journal-title":"Eur. J. Neurosci."},{"key":"10134_CR28","doi-asserted-by":"publisher","first-page":"2380","DOI":"10.1074\/jbc.M008919200","volume":"276","author":"BI Giasson","year":"2001","unstructured":"Giasson, B. I., Murray, I. V. J., Trojanowski, J. Q. & Lee, V. M. Y. A hydrophobic stretch of 12 amino acid residues in the middle of \u03b1-synuclein is essential for filament assembly. J. Biol. Chem. 276, 2380\u20132386 (2001).","journal-title":"J. Biol. Chem."},{"key":"10134_CR29","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1038\/nchem.2361","volume":"7","author":"NP Marotta","year":"2015","unstructured":"Marotta, N. P. et al. O-GlcNAc modification blocks the aggregation and toxicity of the protein \u03b1-synuclein associated with Parkinson\u2019s disease. Nat. Chem. 7, 913\u2013920 (2015).","journal-title":"Nat. Chem."},{"key":"10134_CR30","doi-asserted-by":"publisher","first-page":"3338","DOI":"10.1523\/JNEUROSCI.0285-07.2007","volume":"27","author":"M Periquet","year":"2007","unstructured":"Periquet, M., Fulga, T., Myllykangas, L., Schlossmacher, M. G. & Feany, M. B. Aggregated \u03b1-synuclein mediates dopaminergic neurotoxicity in vivo. J. Neurosci. 27, 3338\u20133346 (2007).","journal-title":"J. Neurosci."},{"key":"10134_CR31","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1110\/ps.073181508","volume":"17","author":"RC Rivers","year":"2008","unstructured":"Rivers, R. C. et al. Molecular determinants of the aggregation behavior of \u03b1- and \u03b2-synuclein. Protein Sci. 17, 887\u2013898 (2008).","journal-title":"Protein Sci."},{"key":"10134_CR32","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1523\/JNEUROSCI.4308-05.2006","volume":"26","author":"LJ Martin","year":"2006","unstructured":"Martin, L. J. et al. Parkinson\u2019s disease \u03b1-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J. Neurosci. 26, 41\u201350 (2006).","journal-title":"J. Neurosci."},{"key":"10134_CR33","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1126\/science.aam9080","volume":"357","author":"LF Burbulla","year":"2017","unstructured":"Burbulla, L. F. et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson\u2019s disease. Science 357, 1255\u20131261 (2017).","journal-title":"Science"},{"key":"10134_CR34","doi-asserted-by":"publisher","first-page":"9089","DOI":"10.1074\/jbc.M710012200","volume":"283","author":"L Devi","year":"2008","unstructured":"Devi, L., Raghavendran, V., Prabhu, B. M., Avadhani, N. G. & Anandatheerthavarada, H. K. Mitochondrial import and accumulation of \u03b1-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J. Biol. Chem. 283, 9089\u20139100 (2008).","journal-title":"J. Biol. Chem."},{"key":"10134_CR35","doi-asserted-by":"publisher","first-page":"3571","DOI":"10.1038\/emboj.2010.223","volume":"29","author":"F Kamp","year":"2010","unstructured":"Kamp, F. et al. Inhibition of mitochondrial fusion by \u03b1-synuclein is rescued by PINK1, Parkin and DJ-1. EMBO J. 29, 3571\u20133589 (2010).","journal-title":"EMBO J."},{"key":"10134_CR36","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1016\/j.biocel.2009.05.008","volume":"41","author":"MS Parihar","year":"2009","unstructured":"Parihar, M. S., Parihar, A., Fujita, M., Hashimoto, M. & Ghafourifar, P. Alpha-synuclein overexpression and aggregation exacerbates impairment of mitochondrial functions by augmenting oxidative stress in human neuroblastoma cells. Int. J. Biochem. Cell Biol. 41, 2015\u20132024 (2009).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"10134_CR37","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/S0002-9440(10)64553-1","volume":"157","author":"LJ Hsu","year":"2000","unstructured":"Hsu, L. J. et al. \u03b1-synuclein promotes mitochondrial deficit and oxidative stress. Am. J. Pathol. 157, 401\u2013410 (2000).","journal-title":"Am. J. Pathol."},{"key":"10134_CR38","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1021\/cb900112v","volume":"4","author":"A \u00c5slund","year":"2009","unstructured":"\u00c5slund, A. et al. Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses NIH Public Access. ACS Chem. Biol. 4, 673\u2013684 (2009).","journal-title":"ACS Chem. Biol."},{"key":"10134_CR39","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1038\/s41593-019-0350-2","volume":"22","author":"SL Giandomenico","year":"2019","unstructured":"Giandomenico, S. L. et al. Cerebral organoids at the air\u2013liquid interface generate diverse nerve tracts with functional output. Nat. Neurosci. 22, 669\u2013679 (2019).","journal-title":"Nat. Neurosci."},{"key":"10134_CR40","doi-asserted-by":"publisher","unstructured":"Garza, R. et al. Activation of transposable elements is linked to a region- and cell-type-specific interferon response in Parkinson\u2019s disease. https:\/\/doi.org\/10.1101\/2025.09.03.673956 (2025).","DOI":"10.1101\/2025.09.03.673956"}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10134-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10134-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10134-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T22:53:02Z","timestamp":1786575182000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-026-10134-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,12]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["10134"],"URL":"https:\/\/doi.org\/10.1038\/s42003-026-10134-x","relation":{},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,12]]},"assertion":[{"value":"30 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"1098"}}