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.

SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome / Banfi, F.; Rubio, A.; Zaghi, M.; Massimino, L.; Fagnocchi, G.; Bellini, E.; Luoni, M.; Cancellieri, C.; Bagliani, A.; Di Resta, C.; Maffezzini, C.; Ianielli, A.; Ferrari, M.; Piazza, R.; Mologni, L.; Broccoli, V.; Sessa, A.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 12:1(2021), p. 4050. [10.1038/s41467-021-24391-3]

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

Banfi F.;Zaghi M.;Luoni M.;Di Resta C.;Ferrari M.;
2021-01-01

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.
2021
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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/122138
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