Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.
Cell
; 187(10): 2446-2464.e22, 2024 May 09.
Article
in En
| MEDLINE
| ID: mdl-38582079
ABSTRACT
Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer's Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tau Proteins
/
Tauopathies
/
Induced Pluripotent Stem Cells
/
Neurons
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell
Year:
2024
Document type:
Article