SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome.
Federica BanfiAlicia RubioMattia ZaghiLuca MassiminoGiulia FagnocchiEdoardo Niccolò BelliniMirko LuoniCinzia CancellieriAnna BaglianiChiara Di RestaCamilla MaffezziniAngelo IanielliMaurizio FerrariRocco Giovanni PiazzaLuca MologniVania BroccoliAlessandro SessaPublished in: Nature communications (2021)
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.
Keyphrases
- dna damage
- oxidative stress
- dna repair
- case report
- endothelial cells
- physical activity
- single cell
- copy number
- mental health
- traumatic brain injury
- early onset
- signaling pathway
- stem cells
- dna methylation
- mesenchymal stem cells
- gene expression
- spinal cord injury
- transcription factor
- cell proliferation
- cell cycle arrest
- binding protein
- subarachnoid hemorrhage
- amino acid
- induced pluripotent stem cells
- stress induced
- living cells
- brain injury
- drug induced