Lithium as a possible therapeutic strategy for Cornelia de Lange syndrome

Abstract

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.

Cohesin Mutations in Cancer: Emerging Therapeutic Targets

“…Hyperactive Wnt signaling leading to increased frequency of myeloid progenitors was shown in Nipbl-depleted zebrafish, and in this study, treatment with the Wnt inhibitor indomethacin ameliorated this phenotype [159]. Lithium, another GSK3 inhibitor, rescued cell proliferation defects in a Drosophila CdLS model and in lymphoblastoid cell lines from CdLS patients [158]. Lithium and other GSK3 inhibitors have been shown be effective inhibitors in several cancers; however, further studies will be required to understand how Wnt agonism could be of therapeutic value in cohesin mutant cells.…”

“…Wnt signaling: Dysregulation of Wnt signaling as an underlying event in cohesin depleted cells has emerged from several studies [80,158,159,185]. We found that cohesin mu-tant MCF10A cells showed increased sensitivity to the glycogen synthase kinase 3 (GSK3) inhibitor LY209031, which stimulates Wnt signaling.…”

Cornelia de Lange Syndrome: From a Disease to a Broader Spectrum

“…WNT signaling alterations have been associated with a plethora of CNS abnormalities and canonical WNT pathway was found to be perturbed in CdLS models [ 32 , 33 , 34 , 35 ]. In the contest of embryonic development, the WNT signaling plays a fundamental role in all steps of development by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells and pluripotent state [ 36 ].…”

“…The disruption of gene regulation during critical steps of early embryonic development contributes to a WNT signaling alterations that has been associated with a plethora of CNS abnormalities. To date, different studies have shown that the WNT canonical pathway is altered in CdLS models [ 32 , 33 , 34 , 35 ], suggesting it and its downstream effectors as a treatment target option.…”

“…Lithium is a well-known drug and an effective therapeutic agent for bipolar disorders [ 62 ], recently implemented for amyotrophic lateral sclerosis treatment as well, and acts as a specific inhibitor of the conserved WNT transducer GSK3 [ 63 ]. Notably, it has been shown that lithium treatment, by modulating the WNT pathway, was able to rescue phenotypes associated with CdLS in nipblb -loss-of-function zebrafish embryos [ 32 ] as well as in Drosophila nipbl model and murine and human in vitro models [ 35 ]. These data suggest that lithium might be used to at least partially ameliorate CdLS phenotype also in CdLS human fetuses, by maternal administration, since it is frequently prescribed to pregnant women for the treatment of bipolar disorder [ 64 ].…”