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.

Banfi, F., Rubio, A., Zaghi, M., Massimino, L., Fagnocchi, G., Bellini, E., et al. (2021). SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome. NATURE COMMUNICATIONS, 12(1) [10.1038/s41467-021-24391-3].

SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome

Massimino L.;Di Resta C.;Piazza R.;Mologni L.;
2021

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.
Articolo in rivista - Articolo scientifico
Abnormalities, Multiple; Carrier Proteins; Cells, Cultured; Craniofacial Abnormalities; Hand Deformities, Congenital; Heredodegenerative Disorders, Nervous System; Humans; Intellectual Disability; Nails, Malformed; Neural Stem Cells; Nuclear Proteins; Organoids; Tumor Suppressor Protein p53; DNA Damage; Mutation;
English
2021
12
1
4050
open
Banfi, F., Rubio, A., Zaghi, M., Massimino, L., Fagnocchi, G., Bellini, E., et al. (2021). SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome. NATURE COMMUNICATIONS, 12(1) [10.1038/s41467-021-24391-3].
File in questo prodotto:
File Dimensione Formato  
Nature Communications 2021 SETBP1 P53.pdf

accesso aperto

Tipologia di allegato: Publisher’s Version (Version of Record, VoR)
Dimensione 6.72 MB
Formato Adobe PDF
6.72 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/345362
Citazioni
  • Scopus 27
  • ???jsp.display-item.citation.isi??? 25
Social impact