Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease.
Cell Death Dis
; 15(1): 4, 2024 01 04.
Article
in En
| MEDLINE
| ID: mdl-38177100
ABSTRACT
Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Neurodegenerative Diseases
/
Amyotrophic Lateral Sclerosis
Limits:
Adult
/
Animals
/
Humans
Language:
En
Journal:
Cell Death Dis
/
Cell death and disease
Year:
2024
Document type:
Article