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Modeling Sporadic Progressive Supranuclear Palsy in 3D Midbrain Organoids : Recapitulating Disease Features for In Vitro Diagnosis and Drug Discovery

Parrotta, Elvira Immacolata ; Lucchino, Valeria ; Zannino, Clara ; Valente, Desirèe ; Scalise, Stefania ; Bressan, Davide ; Benedetto, Giorgia Lucia ; Iazzetta, Maria Roberta ; Talarico, Mariagrazia and Gagliardi, Monica , et al. (2025) In Annals of Neurology
Abstract

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... (More)

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.

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Contribution to journal
publication status
epub
subject
in
Annals of Neurology
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85216343012
  • pmid:39876539
ISSN
0364-5134
DOI
10.1002/ana.27172
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
id
c986e060-157c-4df4-8d42-00de982798ac
date added to LUP
2025-04-09 16:12:55
date last changed
2025-07-17 07:46:32
@article{c986e060-157c-4df4-8d42-00de982798ac,
  abstract     = {{<p>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.</p>}},
  author       = {{Parrotta, Elvira Immacolata and Lucchino, Valeria and Zannino, Clara and Valente, Desirèe and Scalise, Stefania and Bressan, Davide and Benedetto, Giorgia Lucia and Iazzetta, Maria Roberta and Talarico, Mariagrazia and Gagliardi, Monica and Conforti, Francesco and Di Agostino, Silvia and Fiorenzano, Alessandro and Quattrone, Aldo and Cuda, Giovanni and Quattrone, Andrea}},
  issn         = {{0364-5134}},
  language     = {{eng}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Annals of Neurology}},
  title        = {{Modeling Sporadic Progressive Supranuclear Palsy in 3D Midbrain Organoids : Recapitulating Disease Features for In Vitro Diagnosis and Drug Discovery}},
  url          = {{http://dx.doi.org/10.1002/ana.27172}},
  doi          = {{10.1002/ana.27172}},
  year         = {{2025}},
}