SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome.
Nat Commun
; 12(1): 4050, 2021 06 30.
Article
in En
| MEDLINE
| ID: mdl-34193871
ABSTRACT
The investigation of genetic forms of juvenile neurodegeneration could shed light on the causative mechanisms of neuronal loss. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome caused by mutations in the SETBP1 gene, inducing the accumulation of its protein product. SGS features multi-organ involvement with severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here we introduce a human SGS model that displays disease-relevant phenotypes. We show that SGS neural progenitors exhibit aberrant proliferation, deregulation of oncogenes and suppressors, unresolved DNA damage, and resistance to apoptosis. Mechanistically, we demonstrate that high SETBP1 levels inhibit P53 function through the stabilization of SET, which in turn hinders P53 acetylation. We find that the inheritance of unresolved DNA damage in SGS neurons triggers the neurodegenerative process that can be alleviated either by PARP-1 inhibition or by NAD + supplementation. These results implicate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Abnormalities, Multiple
/
DNA Damage
/
Hand Deformities, Congenital
/
Nuclear Proteins
/
Carrier Proteins
/
Tumor Suppressor Protein p53
/
Craniofacial Abnormalities
/
Heredodegenerative Disorders, Nervous System
/
Neural Stem Cells
/
Intellectual Disability
Limits:
Humans
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2021
Document type:
Article
Affiliation country:
Italia