2. Academic Validation
  3. SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome

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

  • Nat Commun. 2021 Jun 30;12(1):4050. doi: 10.1038/s41467-021-24391-3.
Federica Banfi 1 2,  Alicia Rubio 1 2,  Mattia Zaghi 1,  Luca Massimino 1,  Giulia Fagnocchi 1,  Edoardo Bellini 1,  Mirko Luoni 1,  Cinzia Cancellieri 1 3,  Anna Bagliani 4,  Chiara Di Resta 5 6,  Camilla Maffezzini 1,  Angelo Ianielli 1 2,  Maurizio Ferrari 5,  Rocco Piazza 7,  Luca Mologni 7,  Vania Broccoli 1 2,  Alessandro Sessa 8
Affiliations

Affiliations

  • 1 Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • 2 CNR Institute of Neuroscience, Milan, Italy.
  • 3 Human Induced Pluripotent Stem Cells service, Istituto Italiano di Oncologia Molecolare (IFOM), Milan, Italy.
  • 4 Medical Oncology Unit, ASST Ovest Milanese, Legnano Hospital, Legnano, Italy.
  • 5 Vita-Salute San Raffaele University, Milan, Italy.
  • 6 Unit of Genomics for human disease diagnosis, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • 7 Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
  • 8 Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy. sessa.alessandro@hsr.it.
PMID: 34193871 DOI: 10.1038/s41467-021-24391-3
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.

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