KCNJ2 inhibition mitigates mechanical injury in a human brain organoid model of traumatic brain injury.
Cell Stem Cell
; 31(4): 519-536.e8, 2024 Apr 04.
Article
in En
| MEDLINE
| ID: mdl-38579683
ABSTRACT
Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain and which strategies most potently mitigate these processes. We developed a high-intensity ultrasound platform to inflict mechanical injury to induced pluripotent stem cell (iPSC)-derived cortical organoids. Mechanically injured organoids elicit classic hallmarks of TBI, including neuronal death, tau phosphorylation, and TDP-43 nuclear egress. We found that deep-layer neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes cell death. Injured organoids derived from C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes in vitro and in vivo, including in C9ORF72 ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuronal death after brain injury, and we present a scalable, genetically flexible cerebral organoid model that may enable the identification of additional modifiers of mechanical stress.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Neurodegenerative Diseases
/
Potassium Channels, Inwardly Rectifying
/
Frontotemporal Dementia
/
Brain Injuries, Traumatic
/
Amyotrophic Lateral Sclerosis
Limits:
Humans
Language:
En
Journal:
Cell Stem Cell
Year:
2024
Document type:
Article
Country of publication:
Estados Unidos