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.
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DOI：
10.1038/s41467-021-24391-3
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发表时间：
2021-06-30
影响因子：
16.6
通讯作者：
Sessa A
中科院分区：
文献类型：
--
作者：
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
青少年神经退行性变的遗传形式的调查可以揭示神经元丢失的致病机制。Schinzel-Giedion综合征（SGS）是一种致命的发育综合征，由SETBP 1基因突变引起，诱导其蛋白产物的积累。SGS的特点是多器官受累，伴有严重的智力和身体缺陷，至少部分是由于早期神经退行性变。在这里，我们介绍了一个人类SGS模型，显示疾病相关的表型。我们发现，SGS神经祖细胞表现出异常增殖，癌基因和抑制基因的失调，未解决的DNA损伤和抗凋亡。从机制上讲，我们证明了高水平的SETBP 1通过稳定SET抑制P53功能，这反过来又阻碍了P53乙酰化。我们发现SGS神经元中未解决的DNA损伤的遗传触发了神经退行性过程，该过程可以通过PARP-1抑制或NAD +补充来缓解。这些结果表明，SGS中的神经元死亡起源于发育改变，主要是在维护细胞的身份和稳态。Schinzel-Giedion综合征（SGS）是一种致命的发育综合征，其特征是严重的智力和身体缺陷，至少部分是由于早期神经变性。在这里，作者介绍了一种显示疾病相关表型的人类SGS模型，以证明SGS中的神经元死亡起源于发育改变，主要是保护细胞身份和稳态。
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. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome characterized by severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here the authors introduce a human SGS model that displays disease-relevant phenotypes to demonstrate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.
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影响因子：
23.9
作者：
Buckley, Shannon M.;Aranda-Orgilles, Beatriz;Strikoudis, Alexandros;Apostolou, Effie;Loizou, Evangelia;Moran-Crusio, Kelly;Farnsworth, Charles L.;Koller, Antonius A.;Dasgupta, Ramanuj;Silva, Jeffrey C.;Stadtfeld, Matthias;Hochedlinger, Konrad;Chen, Emily I.;Aifantis, Iannis
通讯作者：
Aifantis, Iannis
影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
DOI：
10.1016/s1474-4422(17)30299-5
发表时间：
2017-11
期刊：
The Lancet. Neurology
影响因子：
--
作者：
GBD 2015 Neurological Disorders Collaborator Group
通讯作者：
GBD 2015 Neurological Disorders Collaborator Group
影响因子：
16.6
作者：
Fragola, Giulia;Mabb, Angela M.;Zylka, Mark J.
通讯作者：
Zylka, Mark J.
影响因子：
1.9
作者：
Herenger, Yvan;Stoetzel, Corinne;Dollfus, Helene
通讯作者：
Dollfus, Helene