Lithium as a possible therapeutic strategy for Cornelia de Lange syndrome

Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from the deregulation of developmental pathways, inclusive of the canonical WNT pathway. We...

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Bibliographic Details
Published in:Cell death discovery 2021-02, Vol.7 (1), p.34-34, Article 34
Main Authors: Grazioli, Paolo, Parodi, Chiara, Mariani, Milena, Bottai, Daniele, Di Fede, Elisabetta, Zulueta, Aida, Avagliano, Laura, Cereda, Anna, Tenconi, Romano, Wierzba, Jolanta, Adami, Raffaella, Iascone, Maria, Ajmone, Paola Francesca, Vaccari, Thomas, Gervasini, Cristina, Selicorni, Angelo, Massa, Valentina
Format: Article
Language:English
Subjects:
631/136/142
631/136/1425
692/699/375/366
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Cell proliferation
Central nervous system
Cohesin
Cytology
De Lange syndrome
Embryos
Hindbrain
Life Sciences
Lithium
Lithium chloride
Lymphoblastoid cell lines
Magnetic resonance imaging
Mushroom bodies
Neural stem cells
Phenotypes
Stem cell transplantation
Stem Cells
Wnt protein
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Summary:Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from the deregulation of developmental pathways, inclusive of the canonical WNT pathway. We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin. Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1 . This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.
ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-021-00414-2