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

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.

SETBP1variants outside the degron disrupt DNA-binding and transcription independent of protein abundance to cause a heterogeneous neurodevelopmental disorder

“…Nevertheless, we did not observe overlaps with genes dysregulated in aCML patient cells, nor did we observe any changes in proliferation in fibroblasts derived from individuals carrying recurrent variant p.(Glu858Lys) that has also been reported in individuals with leukaemia 7 . This is consistent with the findings of a recent study where disruption of SET/PP2A pathway was not detected in SGS neural progenitors and cortical organoids 8 , suggesting that the aetiological pathways underlying germline and somatic SETBP1 variants are likely cell type-/tissue-specific. Future studies investigating the spatial and temporal expression of SETBP1 and the functional impact of variants during brain development are much needed to understand the pathways that go awry.…”

“…Nevertheless, the roles of SETBP1 in the developing brain and the pathophysiological pathways underlying germline pathogenic SETBP1 variants remain elusive. Thus far, only three recent studies have investigated the molecular consequences of SETBP1 disruptions in mouse and human neuronal models 8,20,24 , all of which described impairment in cell proliferation as a shared mechanism. Overexpression of human wild type SETBP1 and an SGS variant in mouse embryos via i n utero electroporation disrupted neuronal migration and neurogenesis in the neocortex 20 .…”

“…Intriguingly, overlapping somatic SETBP1 variants have been identified recurrently in several forms of myeloid leukaemia 6,7 . These overlapping somatic variants are more disruptive to the degron, implying a higher functional threshold to cause cancer 6 , and it is thought that germline variants might lead to features similar to cancer cells such as increased proliferation and accumulation in DNA damage but via different cell type-specific pathways 8 .…”

Rare Does Not Mean Worthless: How Rare Diseases Have Shaped Neurodevelopment Research in the NGS Era

“…Later on, many studies took advantage of the combined use of whole transcriptomic and gene network analysis using the iPSC-based modelling of idiopathic and non-syndromic ASD [ 62 , 63 ], rare developmental syndromes [ 64 , 65 ], and other NDDs [ 66 , 67 ]. Here, both neural precursor cells and post-mitotic neurons show the dysregulation of expression in gene categories related to proliferation, intracellular signaling, extracellular matrix, synapsis, chromatin remodeling, differentiation and neurogenesis, and the control of oncogenes and onco-suppressors.…”

“…Independently from the chosen protocol, organoids have so far been extremely useful for investigating early brain development in vitro better, and by implication, the study and understanding of disorders that are related to the early stages of neurodevelopment. As for classical models, organoids have been used extensively to study neurodevelopmental and neuropsychiatric disorders, including microcephaly [ 94 , 102 ], macrocephaly [ 103 ], lissencephaly [ 103 , 104 , 105 ], periventricular heterotopia [ 106 , 107 , 108 ], ASD [ 109 ], schizophrenia [ 110 ], Rett syndrome [ 111 ], fragile X syndrome [ 112 ], frontotemporal dementia [ 113 ], Schinzel–Giedion syndrome [ 65 ], and many others.…”