{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:25:54Z","timestamp":1792801554515,"version":"4.5.0"},"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Yumanity Therapeutics"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    There are currently no preventive or disease-modifying therapies for Parkinson\u2019s Disease (PD). Failures in clinical trials necessitate a re-evaluation of existing pre-clinical models in order to adopt systems that better recapitulate underlying disease mechanisms and better predict clinical outcomes. In recent years, models utilizing patient-derived induced pluripotent stem cells (iPSC) have emerged as attractive models to recapitulate disease-relevant neuropathology\n                    <jats:italic>in vitro<\/jats:italic>\n                    without exogenous overexpression of disease-related pathologic proteins. Here, we utilized iPSC derived from patients with early-onset PD and dementia phenotypes that harbored either a point mutation (A53T) or multiplication at the \u03b1-synuclein\/\n                    <jats:italic>SNCA<\/jats:italic>\n                    gene locus. We generated a three-dimensional (3D) cortical neurosphere culture model to better mimic the tissue microenvironment of the brain. We extensively characterized the differentiation process using quantitative PCR, Western immunoblotting and immunofluorescence staining. Differentiated and aged neurospheres revealed alterations in fatty acid profiles and elevated total and pathogenic phospho-\u03b1-synuclein levels in both A53T and the triplication lines compared to their isogenic control lines. Furthermore, treatment of the neurospheres with a small molecule inhibitor of stearoyl CoA desaturase (SCD) attenuated the protein accumulation and aberrant fatty acid profile phenotypes. Our findings suggest that the 3D cortical neurosphere model is a useful tool to interrogate targets for PD and amenable to test small molecule therapeutics.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0277532","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T14:48:16Z","timestamp":1669906096000},"page":"e0277532","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Patient-derived three-dimensional cortical neurospheres to model Parkinson\u2019s disease"],"prefix":"10.1371","volume":"17","author":[{"given":"Waseem K.","family":"Raja","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Neves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Burke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth J.","family":"Rhodes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikram","family":"Khurana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Scannevin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5515-650X","authenticated-orcid":true,"given":"Chee Yeun","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,12,1]]},"reference":[{"key":"pone.0277532.ref001","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/S1474-4422(18)30295-3","article-title":"Global, regional, and national burden of Parkinson\u2019s disease, 1990\u20132016: a systematic analysis for the Global Burden of Disease Study 2016","volume":"17","author":"E. Ray Dorsey","year":"2018","journal-title":"Lancet Neurol"},{"key":"pone.0277532.ref002","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1038\/nrd.2016.175","article-title":"Screening out irrelevant cell-based models of disease","volume":"15","author":"P. Horvath","year":"2016","journal-title":"Nat Rev Drug Discov"},{"key":"pone.0277532.ref003","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1038\/s41593-018-0236-8","article-title":"Animal models of neurodegenerative diseases","volume":"21","author":"T.M. Dawson","year":"2018","journal-title":"Nat Neurosci"},{"key":"pone.0277532.ref004","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/B978-0-12-813671-3.00009-8","article-title":"Neural tissue microphysiological systems in the era of patient-derived pluripotent stem cells","author":"A.E. Mungenast","year":"2019","journal-title":"Microfluidic Cell Culture Systems"},{"key":"pone.0277532.ref005","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"K. Takahashi","year":"2007","journal-title":"Cell"},{"key":"pone.0277532.ref006","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.ceb.2015.10.008","article-title":"Pluripotent stem cell-based disease modeling: current hurdles and future promise","volume":"37","author":"N. Zeltner","year":"2015","journal-title":"Curr Opin Cell Biol"},{"key":"pone.0277532.ref007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pneurobio.2014.11.003","article-title":"3D in vitro modeling of the central nervous system","volume":"125","author":"A.M. Hopkins","year":"2015","journal-title":"Prog Neurobiol"},{"key":"pone.0277532.ref008","doi-asserted-by":"crossref","first-page":"e0161969","DOI":"10.1371\/journal.pone.0161969","article-title":"Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer\u2019s Disease Phenotypes.","volume":"11","author":"W.K. Raja","year":"2016","journal-title":"PLoS One"},{"key":"pone.0277532.ref009","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3233\/JPD-160779","article-title":"Implication of Alpha-Synuclein Phosphorylation at S129 in Synucleinopathies: What Have We Learned in the Last Decade?","volume":"6","author":"A. Oueslati","year":"2016","journal-title":"J Parkinsons Dis"},{"key":"pone.0277532.ref010","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1038\/s41593-019-0423-2","article-title":"Lewy pathology in Parkinson\u2019s disease consists of crowded organelles and lipid membranes","volume":"22","author":"S.H. Shahmoradian","year":"2019","journal-title":"Nat Neurosci"},{"key":"pone.0277532.ref011","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41531-019-0103-7","article-title":"Parkinson\u2019s disease: proteinopathy or lipidopathy?","volume":"6","author":"S. Fanning","year":"2020","journal-title":"NPJ Parkinsons Dis"},{"key":"pone.0277532.ref012","doi-asserted-by":"crossref","first-page":"7314","DOI":"10.1038\/ncomms8314","article-title":"Parkinson-causing alpha-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation","volume":"6","author":"U. Dettmer","year":"2015","journal-title":"Nat Commun"},{"key":"pone.0277532.ref013","doi-asserted-by":"crossref","first-page":"20760","DOI":"10.1073\/pnas.1903216116","article-title":"Cell models of lipid-rich alpha-synuclein aggregation validate known modifiers of alpha-synuclein biology and identify stearoyl-CoA desaturase","volume":"116","author":"T. Imberdis","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0277532.ref014","doi-asserted-by":"crossref","first-page":"E28","DOI":"10.1152\/ajpendo.90897.2008","article-title":"Biochemical and physiological function of stearoyl- CoA desaturase","volume":"297","author":"C.M. Paton","year":"2009","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"pone.0277532.ref015","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.molcel.2018.11.028","article-title":"Lipidomic Analysis of alpha- Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment","volume":"73","author":"S. Fanning","year":"2018","journal-title":"Mol Cell"},{"key":"pone.0277532.ref016","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/ana.25920","article-title":"A Stearoyl-Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in alpha-Synuclein Mice","volume":"89","author":"S. Nuber","year":"2021","journal-title":"Ann Neurol"},{"key":"pone.0277532.ref017","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1016\/j.celrep.2018.11.028","article-title":"Inhibiting Stearoyl- CoA Desaturase Ameliorates alpha-Synuclein Cytotoxicity","volume":"25","author":"B.M. Vincent","year":"2018","journal-title":"Cell Rep"},{"key":"pone.0277532.ref018","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1002\/mds.27806","article-title":"Longitudinal analyses of cerebrospinal fluid alpha-Synuclein in prodromal and early Parkinson\u2019s disease","volume":"34","author":"B. Mollenhauer","year":"2019","journal-title":"Mov Disord"},{"key":"pone.0277532.ref019","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/ncb748","article-title":"alpha-Synuclein is phosphorylated in synucleinopathy lesions","volume":"4","author":"H. Fujiwara","year":"2002","journal-title":"Nat Cell Biol"},{"key":"pone.0277532.ref020","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1126\/science.1245296","article-title":"Identification and rescue of alpha-synuclein toxicity in Parkinson patient-derived neurons","volume":"342","author":"C.Y. Chung","year":"2013","journal-title":"Science"},{"key":"pone.0277532.ref021","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.neuron.2019.09.001","article-title":"Stress- Induced Cellular Clearance Is Mediated by the SNARE Protein ykt6 and Disrupted by alpha-Synuclein","volume":"104","author":"L.K. Cuddy","year":"2019","journal-title":"Neuron"},{"key":"pone.0277532.ref022","doi-asserted-by":"crossref","first-page":"14280","DOI":"10.1073\/pnas.1900576116","article-title":"Axonal pathology in hPSC-based models of Parkinson\u2019s disease results from loss of Nrf2 transcriptional activity at the Map1b gene locus","volume":"116","author":"C. Czaniecki","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0277532.ref023","doi-asserted-by":"crossref","first-page":"e112413","DOI":"10.1371\/journal.pone.0112413","article-title":"Higher vulnerability and stress sensitivity of neuronal precursor cells carrying an alpha-synuclein gene triplication","volume":"9","author":"A. Flierl","year":"2014","journal-title":"PLoS One"},{"key":"pone.0277532.ref024","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1073\/pnas.1520335113","article-title":"alpha- Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models","volume":"113","author":"J.R. 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Stykel","year":"2018","journal-title":"FASEB J"},{"key":"pone.0277532.ref028","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1038\/s41467-018-04422-2","article-title":"alpha-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson\u2019s disease","volume":"9","author":"M.H.R. Ludtmann","year":"2018","journal-title":"Nat Commun"},{"key":"pone.0277532.ref029","doi-asserted-by":"crossref","first-page":"7693","DOI":"10.1523\/JNEUROSCI.0628-16.2016","article-title":"Activation of beta- Glucocerebrosidase Reduces Pathological alpha-Synuclein and Restores Lysosomal Function in Parkinson\u2019s Patient Midbrain Neurons","volume":"36","author":"J.R. Mazzulli","year":"2016","journal-title":"J Neurosci"},{"key":"pone.0277532.ref030","doi-asserted-by":"crossref","first-page":"7813","DOI":"10.1073\/pnas.1713129115","article-title":"alpha-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies","volume":"115","author":"I. Prots","year":"2018","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0277532","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T14:48:34Z","timestamp":1669906114000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0277532"}},"subtitle":[],"editor":[{"given":"Joseph","family":"Najbauer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,12,1]]},"references-count":30,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0277532","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.08.21.457201","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,1]]}}}