{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T22:53:45Z","timestamp":1791154425402,"version":"4.1.0"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":115,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["npj Parkinsons Dis."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Neuroinflammation is a hallmark of Parkinson\u2019s disease (PD), a progressive neurodegenerative disorder characterized by the accumulation of \u03b1-synuclein and the death of dopaminergic neurons in the substantia nigra. Mutations in\n                    <jats:italic>GBA<\/jats:italic>\n                    are a common risk factor for PD, which can lead to lipid metabolism dysfunction, autophagy\/lysosomal dysregulation, as well as the disruption of other cellular functions. In this study, we investigated the impact of the\n                    <jats:italic>GBA<\/jats:italic>\n                    -\n                    <jats:italic>N370S<\/jats:italic>\n                    mutation and astrocytic reactivity on \u03b1-synuclein pathology and neurotoxicity. To investigate the impact of reactive astrocytes on Parkinson\u2019s disease pathology, we employed iPSC-derived midbrain astrocyte and dopaminergic neuron co-cultures from control and\n                    <jats:italic>GBA-N370S<\/jats:italic>\n                    donors, as well as primary mouse midbrain astrocyte cultures and transcriptomic assays to examine the response of astrocytes to Tumor Necrosis Factor-\u03b1 (TNF\u03b1) and Interferon-\u03b3 (IFN\u03b3). We show that upon inflammatory stimuli astrocytes become reactive, leading to extensive transcriptional changes. RNAseq and experimental validation revealed that calcium transport and homeostasis were severely dysregulated, and functional studies confirmed that\n                    <jats:italic>GBA-N370S<\/jats:italic>\n                    astrocytes exhibited increased calcium release when treated with cytokines. We further explored the impact of inflammation on astrocytic neurosupport in an iPSC-derived dopaminergic neuron and astrocyte co-culture model finding that combined treatment of TNF\u03b1, IFN\u03b3 and \u03b1-synuclein pre-formed fibrils (PFFs) led to neurotoxic effects, suggesting that TNF\u03b1 and IFN\u03b3-activated astrocytes mediate \u03b1-synuclein PFF toxicity. Taken together, these data provide evidence of reduced neurosupport in both control and\n                    <jats:italic>GBA-N370S<\/jats:italic>\n                    iPSC-derived midbrain astrocytes exposed to inflammatory cytokines, suggesting a role for reactive astrocytes in PD pathology.\n                  <\/jats:p>","DOI":"10.1038\/s41531-026-01378-9","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T08:14:02Z","timestamp":1781252042000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reactive astrocytes mediate toxicity in iPSC derived dopaminergic neurons"],"prefix":"10.1038","volume":"12","author":[{"given":"Naroa","family":"Ibarra-Aizpurua","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Olano-Bringas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Vallin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy A.","family":"Crompton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally A.","family":"Cowley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Bengoa-Vergniory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Wade-Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"1378_CR1","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/S1474-4422(21)00030-2","volume":"20","author":"E Tolosa","year":"2021","unstructured":"Tolosa, E., Garrido, A., Scholz, S. W. & Poewe, W. Challenges in the diagnosis of Parkinson\u2019s disease. Lancet Neurol. 20, 385\u2013397 (2021).","journal-title":"Lancet Neurol."},{"key":"1378_CR2","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1007\/s00702-017-1686-y","volume":"124","author":"O-B Tysnes","year":"2017","unstructured":"Tysnes, O.-B. & Storstein, A. Epidemiology of Parkinson\u2019s disease. J. Neural Transm. 124, 901\u2013905 (2017).","journal-title":"J. Neural Transm."},{"key":"1378_CR3","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1016\/j.amjmed.2019.03.001","volume":"132","author":"MT Hayes","year":"2019","unstructured":"Hayes, M. T. Parkinson\u2019s disease and Parkinsonism. Am. J. Med. 132, 802\u2013807 (2019).","journal-title":"Am. J. Med."},{"key":"1378_CR4","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":"1378_CR5","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1038\/s41593-019-0423-2","volume":"22","author":"SH Shahmoradian","year":"2019","unstructured":"Shahmoradian, S. H. et al. Lewy pathology in Parkinson\u2019s disease consists of crowded organelles and lipid membranes. Nat. Neurosci. 22, 1099\u20131109 (2019).","journal-title":"Nat. Neurosci."},{"key":"1378_CR6","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s40035-019-0165-9","volume":"8","author":"SY-Y Pang","year":"2019","unstructured":"Pang, S. Y.-Y. et al. The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson\u2019s disease. Transl. Neurodegener. 8, 23 (2019).","journal-title":"Transl. Neurodegener."},{"key":"1378_CR7","doi-asserted-by":"publisher","first-page":"105663","DOI":"10.1016\/j.nbd.2022.105663","volume":"166","author":"ME Gegg","year":"2022","unstructured":"Gegg, M. E., Menozzi, E. & Schapira, A. H. V. Glucocerebrosidase-associated Parkinson disease: pathogenic mechanisms and potential drug treatments. Neurobiol. Dis. 166, 105663 (2022).","journal-title":"Neurobiol. Dis."},{"key":"1378_CR8","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1093\/qjmed\/89.9.691","volume":"89","author":"O Neudorfer","year":"1996","unstructured":"Neudorfer, O. et al. Occurrence of Parkinson\u2019s syndrome in type 1 Gaucher disease. QJM 89, 691\u2013694 (1996).","journal-title":"QJM"},{"key":"1378_CR9","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.3390\/cells11081261","volume":"11","author":"L Smith","year":"2022","unstructured":"Smith, L. & Schapira, A. H. V. GBA variants and Parkinson disease: mechanisms and treatments. Cells 11, 1261 (2022).","journal-title":"Cells"},{"key":"1378_CR10","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.cell.2011.06.001","volume":"146","author":"JR Mazzulli","year":"2011","unstructured":"Mazzulli, J. R. et al. Gaucher disease glucocerebrosidase and \u03b1-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146, 37\u201352 (2011).","journal-title":"Cell"},{"key":"1378_CR11","doi-asserted-by":"publisher","first-page":"112180","DOI":"10.1016\/j.celrep.2023.112180","volume":"42","author":"H Bogetofte","year":"2023","unstructured":"Bogetofte, H. et al. Post-translational proteomics platform identifies neurite outgrowth impairments in Parkinson\u2019s disease GBA-N370S dopamine neurons. Cell Rep. 42, 112180 (2023).","journal-title":"Cell Rep."},{"key":"1378_CR12","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/ana.23614","volume":"72","author":"ME Gegg","year":"2012","unstructured":"Gegg, M. E. et al. Glucocerebrosidase deficiency in substantia nigra of Parkinson's disease brains. Ann. Neurol. 72, 455\u2013463 (2012).","journal-title":"Ann. Neurol."},{"key":"1378_CR13","doi-asserted-by":"publisher","first-page":"e0252325","DOI":"10.1371\/journal.pone.0252325","volume":"16","author":"NK Polinski","year":"2021","unstructured":"Polinski, N. K. et al. Decreased glucocerebrosidase activity and substrate accumulation of glycosphingolipids in a novel GBA1 D409V knock-in mouse model. PLoS ONE 16, e0252325 (2021).","journal-title":"PLoS ONE"},{"key":"1378_CR14","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/j.nbd.2015.09.009","volume":"82","author":"EM Rocha","year":"2015","unstructured":"Rocha, E. M. et al. Glucocerebrosidase gene therapy prevents \u03b1-synucleinopathy of midbrain dopamine neurons. Neurobiol. Dis. 82, 495\u2013503 (2015).","journal-title":"Neurobiol. Dis."},{"key":"1378_CR15","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/j.stemcr.2016.01.013","volume":"6","author":"HJR Fernandes","year":"2016","unstructured":"Fernandes, H. J. R. et al. ER stress and autophagic perturbations lead to elevated extracellular \u03b1-synuclein in GBA-N370S Parkinson\u2019s iPSC-derived dopamine neurons. Stem Cell Rep. 6, 342\u2013356 (2016).","journal-title":"Stem Cell Rep."},{"key":"1378_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.neuint.2012.10.010","volume":"62","author":"MWJ Cleeter","year":"2013","unstructured":"Cleeter, M. W. J. et al. Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage. Neurochem. Int. 62, 1\u20137 (2013).","journal-title":"Neurochem. Int."},{"key":"1378_CR17","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107044","volume":"26","author":"DA Beccano-Kelly","year":"2023","unstructured":"Beccano-Kelly, D. A. et al. Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson\u2019s iPSC-dopamine neurons. iScience 26, 107044 (2023).","journal-title":"iScience"},{"key":"1378_CR18","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.tins.2019.05.010","volume":"42","author":"T Farfel-Becker","year":"2019","unstructured":"Farfel-Becker, T., Do, J., Tayebi, N. & Sidransky, E. Can GBA1-associated Parkinson disease be modeled in the mouse? Trends Neurosci. 42, 631\u2013643 (2019).","journal-title":"Trends Neurosci."},{"key":"1378_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5028","volume":"5","author":"DC Sch\u00f6ndorf","year":"2014","unstructured":"Sch\u00f6ndorf, D. C. et al. iPSC-derived neurons from GBA1-associated Parkinson\u2019s disease patients show autophagic defects and impaired calcium homeostasis. Nat. Commun. 5, 4028 (2014).","journal-title":"Nat. Commun."},{"key":"1378_CR20","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/s12264-023-01039-4","volume":"39","author":"C He","year":"2023","unstructured":"He, C. & Duan, S. Novel insight into glial biology and diseases. Neurosci. Bull. 39, 365\u2013367 (2023).","journal-title":"Neurosci. Bull."},{"key":"1378_CR21","doi-asserted-by":"publisher","first-page":"2623","DOI":"10.3390\/cells9122623","volume":"9","author":"I Miyazaki","year":"2020","unstructured":"Miyazaki, I. & Asanuma, M. Neuron-astrocyte interactions in Parkinson\u2019s disease. Cells 9, 2623 (2020).","journal-title":"Cells"},{"key":"1378_CR22","first-page":"1","volume":"2016","author":"Y Zhang","year":"2016","unstructured":"Zhang, Y., Tan, F., Xu, P. & Qu, S. Recent advance in the relationship between excitatory amino acid transporters and Parkinson\u2019s disease. Neural Plast. 2016, 1\u20138 (2016).","journal-title":"Neural Plast."},{"key":"1378_CR23","doi-asserted-by":"publisher","first-page":"8618","DOI":"10.1523\/JNEUROSCI.0954-20.2020","volume":"40","author":"T Tsunemi","year":"2020","unstructured":"Tsunemi, T. et al. Astrocytes protect human dopaminergic neurons from \u03b1-synuclein accumulation and propagation. J. Neurosci. 40, 8618\u20138628 (2020).","journal-title":"J. Neurosci."},{"key":"1378_CR24","doi-asserted-by":"publisher","first-page":"106255","DOI":"10.1016\/j.nbd.2023.106255","volume":"185","author":"Z Jiwaji","year":"2023","unstructured":"Jiwaji, Z. & Hardingham, G. E. The consequences of neurodegenerative disease on neuron-astrocyte metabolic and redox interactions. Neurobiol. Dis. 185, 106255 (2023).","journal-title":"Neurobiol. Dis."},{"key":"1378_CR25","doi-asserted-by":"crossref","unstructured":"Huang, J., Li, C. & Shang, H. Astrocytes in neurodegeneration: inspiration from genetics. Front. Neurosci. 16, 882316 (2022).","DOI":"10.3389\/fnins.2022.882316"},{"key":"1378_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39038-8","volume":"14","author":"A de Rus Jacquet","year":"2023","unstructured":"de Rus Jacquet, A. et al. The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson\u2019s disease. Nat. Commun. 14, 3651 (2023).","journal-title":"Nat. Commun."},{"key":"1378_CR27","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.stemcr.2018.12.011","volume":"12","author":"A di Domenico","year":"2019","unstructured":"di Domenico, A. et al. Patient-specific iPSC-derived astrocytes contribute to non-cell-autonomous neurodegeneration in Parkinson\u2019s disease. Stem Cell Rep. 12, 213\u2013229 (2019).","journal-title":"Stem Cell Rep."},{"key":"1378_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-71329-8","volume":"10","author":"T-M Sonninen","year":"2020","unstructured":"Sonninen, T.-M. et al. Metabolic alterations in Parkinson\u2019s disease astrocytes. Sci. Rep. 10, 14474 (2020).","journal-title":"Sci. Rep."},{"key":"1378_CR29","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1038\/s41593-018-0236-8","volume":"21","author":"TM Dawson","year":"2018","unstructured":"Dawson, T. M., Golde, T. E. & Lagier-Tourenne, C. Animal models of neurodegenerative diseases. Nat. Neurosci. 21, 1370\u20131379 (2018).","journal-title":"Nat. Neurosci."},{"key":"1378_CR30","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.nbd.2019.05.006","volume":"129","author":"HDE Booth","year":"2019","unstructured":"Booth, H. D. E. et al. RNA sequencing reveals MMP2 and TGFB1 downregulation in LRRK2 G2019S Parkinson\u2019s iPSC-derived astrocytes. Neurobiol. Dis. 129, 56\u201366 (2019).","journal-title":"Neurobiol. Dis."},{"key":"1378_CR31","doi-asserted-by":"crossref","unstructured":"de Rus Jacquet, A. et al. The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson\u2019s disease. Elife 10, e73062 (2021).","DOI":"10.7554\/eLife.73062"},{"key":"1378_CR32","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/s41531-021-00175-w","volume":"7","author":"P Ramos-Gonzalez","year":"2021","unstructured":"Ramos-Gonzalez, P. et al. Astrocytic atrophy as a pathological feature of Parkinson\u2019s disease with LRRK2 mutation. NPJ Parkinsons Dis. 7, 31 (2021).","journal-title":"NPJ Parkinsons Dis."},{"key":"1378_CR33","doi-asserted-by":"publisher","first-page":"3119","DOI":"10.1007\/s12035-021-02327-8","volume":"58","author":"L Streubel-Gallasch","year":"2021","unstructured":"Streubel-Gallasch, L. et al. Parkinson\u2019s disease\u2013Associated LRRK2 interferes with astrocyte-mediated alpha-synuclein clearance. Mol. Neurobiol. 58, 3119\u20133140 (2021).","journal-title":"Mol. Neurobiol."},{"key":"1378_CR34","doi-asserted-by":"publisher","unstructured":"Crompton, L. A. et al. Efficient and scalable generation of human ventral midbrain astrocytes from human-induced pluripotent stem cells. J. Vis. Exp. https:\/\/doi.org\/10.3791\/62095 (2021).","DOI":"10.3791\/62095"},{"key":"1378_CR35","doi-asserted-by":"publisher","first-page":"114979","DOI":"10.1016\/j.expneurol.2024.114979","volume":"382","author":"SF McComish","year":"2024","unstructured":"McComish, S. F. et al. Reactive astrocytes generated from human iPSC are pro-inflammatory and display altered metabolism. Exp. Neurol. 382, 114979 (2024).","journal-title":"Exp. Neurol."},{"key":"1378_CR36","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3390\/brainsci11020209","volume":"11","author":"U-K Peteri","year":"2021","unstructured":"Peteri, U.-K. et al. Generation of the human pluripotent stem-cell-derived astrocyte model with forebrain identity. Brain Sci. 11, 209 (2021).","journal-title":"Brain Sci."},{"key":"1378_CR37","doi-asserted-by":"publisher","first-page":"327","DOI":"10.3390\/ijms25010327","volume":"25","author":"ES Yarkova","year":"2023","unstructured":"Yarkova, E. S. et al. IPSC-derived astrocytes contribute to in vitro modeling of Parkinson\u2019s disease caused by the GBA1 N370S mutation. Int. J. Mol. Sci. 25, 327 (2023).","journal-title":"Int. J. Mol. Sci."},{"key":"1378_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17876-0","volume":"11","author":"D Agarwal","year":"2020","unstructured":"Agarwal, D. et al. A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders. Nat. Commun. 11, 4183 (2020).","journal-title":"Nat. Commun."},{"key":"1378_CR39","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1093\/oxfordjournals.jbchem.a021780","volume":"122","author":"T Maruyama","year":"1997","unstructured":"Maruyama, T., Kanaji, T., Nakade, S., Kanno, T. & Mikoshiba, K. 2APB, 2-aminoethoxydiphenyl borate, a membrane-penetrable modulator of Ins(1,4,5)P3-induced Ca2+ release. J. Biochem. 122, 498\u2013505 (1997).","journal-title":"J. Biochem."},{"key":"1378_CR40","doi-asserted-by":"crossref","unstructured":"Clarke, L. E. et al. Normal aging induces A1-like astrocyte reactivity. Proc. Natl. Acad. Sci. USA 115, E1896-E1905 (2018).","DOI":"10.1073\/pnas.1800165115"},{"key":"1378_CR41","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1016\/j.stemcr.2018.09.015","volume":"11","author":"S Perriot","year":"2018","unstructured":"Perriot, S. et al. Human induced pluripotent stem cell-derived astrocytes are differentially activated by multiple sclerosis-associated cytokines. Stem Cell Rep. 11, 1199\u20131210 (2018).","journal-title":"Stem Cell Rep."},{"key":"1378_CR42","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1016\/j.stemcr.2017.06.018","volume":"9","author":"J TCW","year":"2017","unstructured":"TCW, J. et al. An efficient platform for astrocyte differentiation from human induced pluripotent stem cells. Stem Cell Rep. 9, 600\u2013614 (2017).","journal-title":"Stem Cell Rep."},{"key":"1378_CR43","doi-asserted-by":"publisher","first-page":"4697","DOI":"10.1073\/pnas.1300398110","volume":"110","author":"A Serio","year":"2013","unstructured":"Serio, A. et al. Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy. Proc. Natl. Acad. Sci. USA 110, 4697\u20134702 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"1378_CR44","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/s41593-022-01061-1","volume":"25","author":"T Kamath","year":"2022","unstructured":"Kamath, T. et al. Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson\u2019s disease. Nat. Neurosci. 25, 588\u2013595 (2022).","journal-title":"Nat. Neurosci."},{"key":"1378_CR45","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/nrn.2016.178","volume":"18","author":"DJ Surmeier","year":"2017","unstructured":"Surmeier, D. J., Obeso, J. A. & Halliday, G. M. Selective neuronal vulnerability in Parkinson disease. Nat. Rev. Neurosci. 18, 101\u2013113 (2017).","journal-title":"Nat. Rev. Neurosci."},{"key":"1378_CR46","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/nature21029","volume":"541","author":"SA Liddelow","year":"2017","unstructured":"Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481\u2013487 (2017).","journal-title":"Nature"},{"key":"1378_CR47","doi-asserted-by":"crossref","unstructured":"Labib, D. et al. Proteomic alterations and novel markers of neurotoxic reactive astrocytes in human induced pluripotent stem cell models. Front. Mol. Neurosci. 15, 870085 (2022).","DOI":"10.3389\/fnmol.2022.870085"},{"key":"1378_CR48","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.neuron.2020.05.014","volume":"107","author":"L Barbar","year":"2020","unstructured":"Barbar, L. et al. CD49f is a novel marker of functional and reactive human iPSC-derived astrocytes. Neuron 107, 436\u2013453.e12 (2020).","journal-title":"Neuron"},{"key":"1378_CR49","doi-asserted-by":"publisher","first-page":"104647","DOI":"10.1016\/j.nbd.2019.104647","volume":"134","author":"E Aflaki","year":"2020","unstructured":"Aflaki, E. et al. A characterization of Gaucher iPS-derived astrocytes: potential implications for Parkinson\u2019s disease. Neurobiol. Dis. 134, 104647 (2020).","journal-title":"Neurobiol. Dis."},{"key":"1378_CR50","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.ceca.2017.06.008","volume":"70","author":"E Pchitskaya","year":"2018","unstructured":"Pchitskaya, E., Popugaeva, E. & Bezprozvanny, I. Calcium signaling and molecular mechanisms underlying neurodegenerative diseases. Cell Calcium 70, 87\u201394 (2018).","journal-title":"Cell Calcium"},{"key":"1378_CR51","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/1750-1326-4-20","volume":"4","author":"P Marambaud","year":"2009","unstructured":"Marambaud, P., Dreses-Werringloer, U. & Vingtdeux, V. Calcium signaling in neurodegeneration. Mol. Neurodegener. 4, 20 (2009).","journal-title":"Mol. Neurodegener."},{"key":"1378_CR52","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-021-00868-6","volume":"14","author":"G Panattoni","year":"2021","unstructured":"Panattoni, G. et al. Diverse inflammatory threats modulate astrocytes Ca2+ signaling via connexin43 hemichannels in organotypic spinal slices. Mol. Brain 14, 159 (2021).","journal-title":"Mol. Brain"},{"key":"1378_CR53","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.tcb.2024.08.007","volume":"35","author":"A Larra\u00f1aga-SanMiguel","year":"2025","unstructured":"Larra\u00f1aga-SanMiguel, A., Bengoa-Vergniory, N. & Flores-Romero, H. Crosstalk between mitochondria\u2013ER contact sites and the apoptotic machinery as a novel health meter. Trends Cell Biol. 35, 33\u201345 (2025).","journal-title":"Trends Cell Biol."},{"key":"1378_CR54","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22113-3","volume":"12","author":"S Kim","year":"2021","unstructured":"Kim, S., Wong, Y. C., Gao, F. & Krainc, D. Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson\u2019s disease. Nat. Commun. 12, 1807 (2021).","journal-title":"Nat. Commun."},{"key":"1378_CR55","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1038\/s41586-023-06935-3","volume":"626","author":"EG Cameron","year":"2024","unstructured":"Cameron, E. G. et al. A molecular switch for neuroprotective astrocyte reactivity. Nature 626, 574\u2013582 (2024).","journal-title":"Nature"},{"key":"1378_CR56","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-53414-9","volume":"9","author":"T Hyv\u00e4rinen","year":"2019","unstructured":"Hyv\u00e4rinen, T. et al. Co-stimulation with IL-1\u03b2 and TNF-\u03b1 induces an inflammatory reactive astrocyte phenotype with neurosupportive characteristics in a human pluripotent stem cell model system. Sci. Rep. 9, 16944 (2019).","journal-title":"Sci. Rep."},{"key":"1378_CR57","doi-asserted-by":"crossref","unstructured":"Yang, Y. et al. Therapeutic functions of astrocytes to treat \u03b1-synuclein pathology in Parkinson\u2019s disease. Proc. Natl. Acad. Sci. USA 119, e2110746119 (2022).","DOI":"10.1073\/pnas.2110746119"},{"key":"1378_CR58","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-04049-0","volume":"12","author":"T-W Chou","year":"2021","unstructured":"Chou, T.-W. et al. Fibrillar \u03b1-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-\u03baB. Cell Death Dis. 12, 756 (2021).","journal-title":"Cell Death Dis."},{"key":"1378_CR59","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1007\/s00401-019-02010-2","volume":"138","author":"J Alegre-Abarrategui","year":"2019","unstructured":"Alegre-Abarrategui, J. et al. Selective vulnerability in \u03b1-synucleinopathies. Acta Neuropathol. 138, 681\u2013704 (2019).","journal-title":"Acta Neuropathol."},{"key":"1378_CR60","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1007\/s40778-016-0049-1","volume":"2","author":"G Tyzack","year":"2016","unstructured":"Tyzack, G., Lakatos, A. & Patani, R. Human stem cell-derived astrocytes: specification and relevance for neurological disorders. Curr. Stem Cell Rep. 2, 236\u2013247 (2016).","journal-title":"Curr. Stem Cell Rep."},{"key":"1378_CR61","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.jneumeth.2019.03.013","volume":"320","author":"J Prah","year":"2019","unstructured":"Prah, J. et al. A novel serum free primary astrocyte culture method that mimic quiescent astrocyte phenotype. J. Neurosci. Methods 320, 50\u201363 (2019).","journal-title":"J. Neurosci. Methods"},{"key":"1378_CR62","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42107-7","volume":"14","author":"AD Klein","year":"2023","unstructured":"Klein, A. D. & Outeiro, T. F. Glucocerebrosidase mutations disrupt the lysosome and now the mitochondria. Nat. Commun. 14, 6383 (2023).","journal-title":"Nat. Commun."},{"key":"1378_CR63","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-05633-1","volume":"7","author":"S Fedele","year":"2017","unstructured":"Fedele, S. et al. Expansion of human midbrain floor plate progenitors from induced pluripotent stem cells increases dopaminergic neuron differentiation potential. Sci. Rep. 7, 6036 (2017).","journal-title":"Sci. Rep."},{"key":"1378_CR64","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1038\/s41531-024-00694-2","volume":"10","author":"QB Do","year":"2024","unstructured":"Do, Q. B. et al. Early deficits in an in vitro striatal microcircuit model carrying the Parkinson\u2019s GBA-N370S mutation. NPJ Parkinsons Dis 10, 82 (2024).","journal-title":"NPJ Parkinsons Dis"},{"key":"1378_CR65","doi-asserted-by":"crossref","unstructured":"Luchena, C. et al. A neuron, microglia, and astrocyte triple co-culture model to study Alzheimer\u2019s disease. Front. Aging Neurosci. 14, 844534 (2022).","DOI":"10.3389\/fnagi.2022.844534"},{"key":"1378_CR66","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18689-x","volume":"11","author":"N Bengoa-Vergniory","year":"2020","unstructured":"Bengoa-Vergniory, N. et al. CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson\u2019s disease. Nat. Commun. 11, 4885 (2020).","journal-title":"Nat. Commun."},{"key":"1378_CR67","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.stemcr.2020.05.003","volume":"15","author":"A Hedegaard","year":"2020","unstructured":"Hedegaard, A. et al. Pro-maturational effects of human iPSC-derived cortical astrocytes upon iPSC-derived cortical neurons. Stem Cell Rep. 15, 38\u201351 (2020).","journal-title":"Stem Cell Rep."},{"key":"1378_CR68","doi-asserted-by":"publisher","first-page":"4355","DOI":"10.1038\/s41380-022-01663-y","volume":"27","author":"J Krauskopf","year":"2022","unstructured":"Krauskopf, J. et al. Transcriptomics analysis of human iPSC-derived dopaminergic neurons reveals a novel model for sporadic Parkinson\u2019s disease. Mol. Psychiatry 27, 4355\u20134367 (2022).","journal-title":"Mol. Psychiatry"},{"key":"1378_CR69","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1007\/s12015-022-10332-0","volume":"18","author":"AT Semeano","year":"2022","unstructured":"Semeano, A. T. et al. Effects of magnetite nanoparticles and static magnetic field on neural differentiation of pluripotent stem cells. Stem Cell Rev. Rep. 18, 1337\u20131354 (2022).","journal-title":"Stem Cell Rev. Rep."},{"key":"1378_CR70","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.stem.2018.10.023","volume":"24","author":"C Lang","year":"2019","unstructured":"Lang, C. et al. Single-cell sequencing of iPSC-dopamine neurons reconstructs disease progression and identifies HDAC4 as a regulator of Parkinson cell phenotypes. Cell Stem Cell 24, 93\u2013106.e6 (2019).","journal-title":"Cell Stem Cell"},{"key":"1378_CR71","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-09362-3","volume":"7","author":"W Haenseler","year":"2017","unstructured":"Haenseler, W. et al. Excess \u03b1-synuclein compromises phagocytosis in iPSC-derived macrophages. Sci. Rep. 7, 9003 (2017).","journal-title":"Sci. Rep."}],"container-title":["npj Parkinson's Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41531-026-01378-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41531-026-01378-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41531-026-01378-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T22:38:24Z","timestamp":1791153504000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41531-026-01378-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,12]]},"references-count":71,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1378"],"URL":"https:\/\/doi.org\/10.1038\/s41531-026-01378-9","relation":{},"ISSN":["2373-8057"],"issn-type":[{"value":"2373-8057","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,12]]},"assertion":[{"value":"3 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 April 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 June 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":"240"}}