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

Federica Banfi, Alicia Rubio, Mattia Zaghi, Luca Massimino, Giulia Fagnocchi, Edoardo Bellini, Mirko Luoni, Cinzia Cancellieri, Anna Bagliani, Chiara Di Resta, Camilla Maffezzini, Angelo Ianielli, Maurizio Ferrari, Rocco Piazza, Luca Mologni, Vania Broccoli and Alessandro Sessa ()
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Federica Banfi: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Alicia Rubio: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Mattia Zaghi: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Luca Massimino: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Giulia Fagnocchi: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Edoardo Bellini: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Mirko Luoni: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Cinzia Cancellieri: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Anna Bagliani: Medical Oncology Unit, ASST Ovest Milanese, Legnano Hospital
Chiara Di Resta: Vita-Salute San Raffaele University
Camilla Maffezzini: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Angelo Ianielli: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Maurizio Ferrari: Vita-Salute San Raffaele University
Rocco Piazza: University of Milano-Bicocca
Luca Mologni: University of Milano-Bicocca
Vania Broccoli: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Alessandro Sessa: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24391-3

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