Modeling Sporadic Progressive Supranuclear Palsy in 3D Midbrain Organoids: Recapitulating Disease Features for In Vitro Diagnosis and Drug Discovery
Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP is challenging due to the lack of disease models reproducing its key pathological features. This study aimed to...
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| Published in | Annals of neurology Vol. 97; no. 5; pp. 845 - 859 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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United States
Wiley Subscription Services, Inc
01.05.2025
John Wiley & Sons, Inc |
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| Abstract | Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP is challenging due to the lack of disease models reproducing its key pathological features. This study aimed to model sporadic PSP-Richardson's syndrome (PSP-RS) using multi-donor midbrain organoids (MOs).
The MOs were generated by pooling induced pluripotent stem cells (iPSCs) from 4 patients with sporadic probable PSP-RS and compared them with MOs from 3 healthy control (HC) subjects. We performed comprehensive analyses of MOs over 120 days to assess neuronal death, reactive gliosis, and the accumulation of 4R-tau and hyperphosphorylated tau forms (pThr231, pSer396, pThr181, and pSer202/pThr205 [AT8]) using immunofluorescence microscopy and Western blot. On day 90, immunohistochemical analysis using pSer396 and AT8 antibodies was conducted to assess disease pathology.
PSP-derived MOs showed progressive size reduction compared with HC-derived MOs, linked to upregulated apoptosis-related mRNA markers. Dopaminergic neuron degeneration was marked by decreased tyrosine hydroxylase (TH) and increased neurofilament light chain (NfL). Immunofluorescence and Western blot revealed accumulation of all investigated tau forms with a peak at 90 days, along with a significant rise in GFAP-positive cells in PSP-derived MOs. Immunochemistry confirmed typical PSP histological alterations, such as neurofibrillary tangles and tufted-shaped astrocytes, absent in HC-derived organoids.
We developed a robust in vitro PSP model reproducing the key molecular and histologic features of the disease. This result holds promise for advancing basic and clinical research in PSP, paving the way for in vitro molecular diagnosis and identification of novel therapeutic targets. ANN NEUROL 2025;97:845-859. |
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| AbstractList | Objective: Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP is challenging due to the lack of disease models reproducing its key pathological features. This study aimed to model sporadic PSP-Richardson's syndrome (PSP-RS) using multi-donor midbrain organoids (MOs). Methods: The MOs were generated by pooling induced pluripotent stem cells (iPSCs) from 4 patients with sporadic probable PSP-RS and compared them with MOs from 3 healthy control (HC) subjects. We performed comprehensive analyses of MOs over 120 days to assess neuronal death, reactive gliosis, and the accumulation of 4R-tau and hyperphosphorylated tau forms (pThr231, pSer396, pThr181, and pSer202/pThr205 [AT8]) using immunofluorescence microscopy and Western blot. On day 90, immunohistochemical analysis using pSer396 and AT8 antibodies was conducted to assess disease pathology. Results: PSP-derived MOs showed progressive size reduction compared with HC-derived MOs, linked to upregulated apoptosis-related mRNA markers. Dopaminergic neuron degeneration was marked by decreased tyrosine hydroxylase (TH) and increased neurofilament light chain (NfL). Immunofluorescence and Western blot revealed accumulation of all investigated tau forms with a peak at 90 days, along with a significant rise in GFAP-positive cells in PSP-derived MOs. Immunochemistry confirmed typical PSP histological alterations, such as neurofibrillary tangles and tufted-shaped astrocytes, absent in HC-derived organoids. Interpretation: We developed a robust in vitro PSP model reproducing the key molecular and histologic features of the disease. This result holds promise for advancing basic and clinical research in PSP, paving the way for in vitro molecular diagnosis and identification of novel therapeutic targets. ANN NEUROL 2025. Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP is challenging due to the lack of disease models reproducing its key pathological features. This study aimed to model sporadic PSP-Richardson's syndrome (PSP-RS) using multi-donor midbrain organoids (MOs). The MOs were generated by pooling induced pluripotent stem cells (iPSCs) from 4 patients with sporadic probable PSP-RS and compared them with MOs from 3 healthy control (HC) subjects. We performed comprehensive analyses of MOs over 120 days to assess neuronal death, reactive gliosis, and the accumulation of 4R-tau and hyperphosphorylated tau forms (pThr231, pSer396, pThr181, and pSer202/pThr205 [AT8]) using immunofluorescence microscopy and Western blot. On day 90, immunohistochemical analysis using pSer396 and AT8 antibodies was conducted to assess disease pathology. PSP-derived MOs showed progressive size reduction compared with HC-derived MOs, linked to upregulated apoptosis-related mRNA markers. Dopaminergic neuron degeneration was marked by decreased tyrosine hydroxylase (TH) and increased neurofilament light chain (NfL). Immunofluorescence and Western blot revealed accumulation of all investigated tau forms with a peak at 90 days, along with a significant rise in GFAP-positive cells in PSP-derived MOs. Immunochemistry confirmed typical PSP histological alterations, such as neurofibrillary tangles and tufted-shaped astrocytes, absent in HC-derived organoids. We developed a robust in vitro PSP model reproducing the key molecular and histologic features of the disease. This result holds promise for advancing basic and clinical research in PSP, paving the way for in vitro molecular diagnosis and identification of novel therapeutic targets. ANN NEUROL 2025;97:845-859. Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP is challenging due to the lack of disease models reproducing its key pathological features. This study aimed to model sporadic PSP-Richardson's syndrome (PSP-RS) using multi-donor midbrain organoids (MOs).OBJECTIVEProgressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP is challenging due to the lack of disease models reproducing its key pathological features. This study aimed to model sporadic PSP-Richardson's syndrome (PSP-RS) using multi-donor midbrain organoids (MOs).The MOs were generated by pooling induced pluripotent stem cells (iPSCs) from 4 patients with sporadic probable PSP-RS and compared them with MOs from 3 healthy control (HC) subjects. We performed comprehensive analyses of MOs over 120 days to assess neuronal death, reactive gliosis, and the accumulation of 4R-tau and hyperphosphorylated tau forms (pThr231, pSer396, pThr181, and pSer202/pThr205 [AT8]) using immunofluorescence microscopy and Western blot. On day 90, immunohistochemical analysis using pSer396 and AT8 antibodies was conducted to assess disease pathology.METHODSThe MOs were generated by pooling induced pluripotent stem cells (iPSCs) from 4 patients with sporadic probable PSP-RS and compared them with MOs from 3 healthy control (HC) subjects. We performed comprehensive analyses of MOs over 120 days to assess neuronal death, reactive gliosis, and the accumulation of 4R-tau and hyperphosphorylated tau forms (pThr231, pSer396, pThr181, and pSer202/pThr205 [AT8]) using immunofluorescence microscopy and Western blot. On day 90, immunohistochemical analysis using pSer396 and AT8 antibodies was conducted to assess disease pathology.PSP-derived MOs showed progressive size reduction compared with HC-derived MOs, linked to upregulated apoptosis-related mRNA markers. Dopaminergic neuron degeneration was marked by decreased tyrosine hydroxylase (TH) and increased neurofilament light chain (NfL). Immunofluorescence and Western blot revealed accumulation of all investigated tau forms with a peak at 90 days, along with a significant rise in GFAP-positive cells in PSP-derived MOs. Immunochemistry confirmed typical PSP histological alterations, such as neurofibrillary tangles and tufted-shaped astrocytes, absent in HC-derived organoids.RESULTSPSP-derived MOs showed progressive size reduction compared with HC-derived MOs, linked to upregulated apoptosis-related mRNA markers. Dopaminergic neuron degeneration was marked by decreased tyrosine hydroxylase (TH) and increased neurofilament light chain (NfL). Immunofluorescence and Western blot revealed accumulation of all investigated tau forms with a peak at 90 days, along with a significant rise in GFAP-positive cells in PSP-derived MOs. Immunochemistry confirmed typical PSP histological alterations, such as neurofibrillary tangles and tufted-shaped astrocytes, absent in HC-derived organoids.We developed a robust in vitro PSP model reproducing the key molecular and histologic features of the disease. This result holds promise for advancing basic and clinical research in PSP, paving the way for in vitro molecular diagnosis and identification of novel therapeutic targets. ANN NEUROL 2025.INTERPRETATIONWe developed a robust in vitro PSP model reproducing the key molecular and histologic features of the disease. This result holds promise for advancing basic and clinical research in PSP, paving the way for in vitro molecular diagnosis and identification of novel therapeutic targets. ANN NEUROL 2025. ObjectiveProgressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP is challenging due to the lack of disease models reproducing its key pathological features. This study aimed to model sporadic PSP‐Richardson's syndrome (PSP‐RS) using multi‐donor midbrain organoids (MOs).MethodsThe MOs were generated by pooling induced pluripotent stem cells (iPSCs) from 4 patients with sporadic probable PSP‐RS and compared them with MOs from 3 healthy control (HC) subjects. We performed comprehensive analyses of MOs over 120 days to assess neuronal death, reactive gliosis, and the accumulation of 4R‐tau and hyperphosphorylated tau forms (pThr231, pSer396, pThr181, and pSer202/pThr205 [AT8]) using immunofluorescence microscopy and Western blot. On day 90, immunohistochemical analysis using pSer396 and AT8 antibodies was conducted to assess disease pathology.ResultsPSP‐derived MOs showed progressive size reduction compared with HC‐derived MOs, linked to upregulated apoptosis‐related mRNA markers. Dopaminergic neuron degeneration was marked by decreased tyrosine hydroxylase (TH) and increased neurofilament light chain (NfL). Immunofluorescence and Western blot revealed accumulation of all investigated tau forms with a peak at 90 days, along with a significant rise in GFAP‐positive cells in PSP‐derived MOs. Immunochemistry confirmed typical PSP histological alterations, such as neurofibrillary tangles and tufted‐shaped astrocytes, absent in HC‐derived organoids.InterpretationWe developed a robust in vitro PSP model reproducing the key molecular and histologic features of the disease. This result holds promise for advancing basic and clinical research in PSP, paving the way for in vitro molecular diagnosis and identification of novel therapeutic targets. ANN NEUROL 2025;97:845–859 |
| Author | Scalise, Stefania Zannino, Clara Quattrone, Aldo Benedetto, Giorgia Lucia Cuda, Giovanni Di Agostino, Silvia Valente, Desirèe Conforti, Francesco Talarico, Mariagrazia Fiorenzano, Alessandro Lucchino, Valeria Bressan, Davide Parrotta, Elvira Immacolata Iazzetta, Maria Roberta Gagliardi, Monica Quattrone, Andrea |
| AuthorAffiliation | 1 Laboratory of Stem Cells, Department of Medical and Surgical Sciences University “Magna Graecia” Catanzaro Italy 6 Neuroscience Research Center, Department of Medical and Surgical Sciences University “Magna Graecia” Catanzaro Italy 7 Division of Pathological Anatomy Annunziata Hospital Cosenza Italy 9 Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund, Stem Cell Center Lund University Lund Sweden 2 Department of Experimental and Clinical Medicine University “Magna Graecia” Catanzaro Italy 10 Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II Naples Italy 3 Laboratory of Stem Cells and Cancer Genomics Department of Cellular, Computational and Integrative Biology (CIBIO) University of Trento Trento Italy 4 Stem Cell Fate Laboratory, Institute of Genetics and Biophysics “A. Buzzati Traverso,” IGB‐CNR Naples Italy 8 Department of Health Sciences University “Magna Graecia” Catanzaro |
| AuthorAffiliation_xml | – name: 9 Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund, Stem Cell Center Lund University Lund Sweden – name: 10 Department of Molecular Medicine and Medical Biotechnology University of Naples Federico II Naples Italy – name: 2 Department of Experimental and Clinical Medicine University “Magna Graecia” Catanzaro Italy – name: 6 Neuroscience Research Center, Department of Medical and Surgical Sciences University “Magna Graecia” Catanzaro Italy – name: 4 Stem Cell Fate Laboratory, Institute of Genetics and Biophysics “A. Buzzati Traverso,” IGB‐CNR Naples Italy – name: 8 Department of Health Sciences University “Magna Graecia” Catanzaro Italy – name: 1 Laboratory of Stem Cells, Department of Medical and Surgical Sciences University “Magna Graecia” Catanzaro Italy – name: 5 Department of Precision Medicine University of Campania “Luigi Vanvitelli” Naples Italy – name: 7 Division of Pathological Anatomy Annunziata Hospital Cosenza Italy – name: 3 Laboratory of Stem Cells and Cancer Genomics Department of Cellular, Computational and Integrative Biology (CIBIO) University of Trento Trento Italy |
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| Copyright | 2025 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. 2025. This article is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2025 The Author(s). published by Wiley Periodicals LLC on behalf of American Neurological Association. |
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| CorporateAuthor | MultiPark: Multidisciplinary research focused on Parkinson's disease Lunds universitet Institutionen för experimentell medicinsk vetenskap Profile areas and other strong research environments Lund University Developmental and Regenerative Neurobiology StemTherapy: National Initiative on Stem Cells for Regenerative Therapy Strategiska forskningsområden (SFO) Department of Experimental Medical Science Faculty of Medicine Strategic research areas (SRA) Utvecklings- och regenerativ neurobiologi Medicinska fakulteten Profilområden och andra starka forskningsmiljöer |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 [Correction added on February 01, 2025 after first online publication: The affiliations number 10 for Alessandro Fiorenzano has been revised in the version]. These authors contributed equally to this study Elvira Immacolata Parrotta, Valeria Lucchino, and Clara Zannino. |
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| Snippet | Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes.... ObjectiveProgressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted... Objective: Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted... |
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| SubjectTerms | Accumulation Aged Apoptosis Astrocytes Basic Medicine Degeneration Diagnosis Dopamine receptors Drug Discovery - methods Female Glial fibrillary acidic protein Gliosis Humans Immunofluorescence Induced Pluripotent Stem Cells - pathology Inhibitory postsynaptic potentials Male Medical and Health Sciences Medicin och hälsovetenskap Medicinska och farmaceutiska grundvetenskaper Mesencephalon Mesencephalon - metabolism Mesencephalon - pathology Middle Aged mRNA Neurodegeneration Neurodegenerative diseases Neurofibrillary tangles Neurosciences Neurovetenskaper Organoids Organoids - metabolism Organoids - pathology Pluripotency Progressive supranuclear palsy Stem cells Supranuclear Palsy, Progressive - diagnosis Supranuclear Palsy, Progressive - drug therapy Supranuclear Palsy, Progressive - metabolism Supranuclear Palsy, Progressive - pathology Tau protein tau Proteins - metabolism Therapeutic targets Tyrosine Tyrosine 3-monooxygenase |
| Title | Modeling Sporadic Progressive Supranuclear Palsy in 3D Midbrain Organoids: Recapitulating Disease Features for In Vitro Diagnosis and Drug Discovery |
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