Neuropathologic and transcriptomic analysis reveals abnormal stress response in sporadic progressive supranuclear palsy autopsy brain tissue and human iPSC‐derived midbrain organoids
SnRNA-seq and neurohistological data reveals ISR dysregulation in disease-affected cell types in PSP brain tissue. ISR activation positively associates with tau burden in vulnerable brain regions in PSP, providing a potential mechanistic link with EIF2AK3 genetic risk. PSP patient-derived organoids recapitulate key disease-relevant features, including elevation of toxic tau proteoforms and ISR dysregulation. This sporadic PSP organoid model will provide insight into cell-type specific drivers of neurodegeneration that underlie sporadic tauopathy.
Authors
- Ruth H. Walker (ORCID: https://orcid.org/0000-0002-8366-072X)
- Won‐Min Song (ORCID: https://orcid.org/0000-0003-0948-119X)
- Megan A. Iida
- Alessandra Cervera
- Diana K. Dangoor
- Kurt Farrell (ORCID: https://orcid.org/0000-0001-6955-7278)
- Tim Ahfeldt (ORCID: https://orcid.org/0000-0001-6377-7376)
- Thomas D. Christie
- Gustavo Morrone Parfitt (ORCID: https://orcid.org/0000-0003-0168-4099)
- Giulietta Riboldi (ORCID: https://orcid.org/0000-0003-0322-5718)
- Lily Sarrafha (ORCID: https://orcid.org/0000-0002-6168-2119)
- Margaret M. Krassner (ORCID: https://orcid.org/0009-0007-6443-2127)
- John F. Crary (ORCID: https://orcid.org/0000-0002-0556-293X)
- SoongHo Kim
- Sally Temple (ORCID: https://orcid.org/0000-0001-7301-783X)
- Kristen Whitney (ORCID: https://orcid.org/0000-0002-1578-6339)
- Steven J. Frucht (ORCID: https://orcid.org/0000-0002-4653-0491)
- Sean Thomas Delica
- Bin Zhang (ORCID: https://orcid.org/0000-0002-9549-5653)
- Ana C. Pereira (ORCID: https://orcid.org/0000-0003-2524-7969)
- Claudia De Sanctis (ORCID: https://orcid.org/0000-0002-9318-7323)
- Hadley A. Walsh
- Abhijeet Sharma
- Grace A. Selecky
- V. Flores Almazan
Institutions
- Allen Institute for Brain Science (US)
- Center for Information Technology (US)
- Neural Stem Cell Institute (US)
- James J. Peters VA Medical Center (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1002/alz.093229
- Primary Topic
- S100 Proteins and Annexins
- Type
- article
- Field-Weighted Citation Impact
- 0.00