Abstract
Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that affects almost any organ, including the central nervous system. It leads to a wide range of neurodevelopmental delays, and there are currently no available clinical treatments. CdLS is caused by pathogenic variants in one of the 7 genes coding for the cohesin complex, a multimeric structure responsible for sister chromatid cohesion, or for cohesin ring-interacting proteins. Additionally, altered regulation of molecular pathways during development, including the canonical WNT pathway, can cause CdLS malformations. In our study, we evaluated the positive effects of using lithium as an activator of the canonical WNT pathway to ameliorate neural CdLS phenotype. We have exploited accurate two-dimensional (2D) and three-dimensional (3D) human central nervous system in vitro models representing disease-related neurobiological phenotypes: induced pluripotent stem cells of human origin (hiPSCs) differentiated into neural precursors, neurons, and brain organoids (BOs). CdLS models demonstrate alterations in proliferation and differentiation capabilities when mimicking HDAC8 haploinsufficiency. Furthermore, RNA-seq analysis of BOs revealed that both neuronal differentiation and the WNT pathway are downregulated when treated with the HDAC8 inhibitor alone. Following lithium treatment, cells show an enhanced ability to differentiate into the neuronal lineage. Additionally, our working hypothesis is that a specific mechanism may exist that, by connecting lipid metabolism, canonical WNT pathway, and cell death, results in typical CdLS neurodevelopmental deficits.
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Data availability
The datasets generated during and/or analysed during the current study, in particular the raw FASTQ sequences, are available in the BioStudies-ArrayExpress database (https://www.ebi.ac.uk/biostudies/arrayexpress) under accession number E-MTAB-15615.
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Acknowledgements
This work was supported by: Cariplo and Telethon Foundation Alliance GJC21149 (VM and CG); Università degli Studi di Milano intramural funding; Aldo Ravelli Center for Neurotechnology and Experimental Brain Therapeutics (to VM and CG); AL supported by Fondazione Veronesi; CP postdoctoral fellowship is supported by Cariplo and Telethon Foundation Alliance GJC21149 (VM and CG); Doctoral Program in Translational Medicine of the University of Milan fellowship to ET. Support has been granted also by PE00000006 “PNRR MUR-M4C2-MNESYS—A multiscale integrated approach to the study of the nervous system in health and disease (MNESYS)” - EXTENDED PARTNERSHIP #, SPOKE 6, CASCADE CALL from PNRR, Mission 4, Component 2, Investment Grant Agreement: D33C22001340002 (to LC). Microscopy observations were carried out at the Advanced Microscopy Facility Platform—UNItech NOLIMITS—University of Milan. The authors would also like to express their deepest gratitude to CdLS patients and families for constant support and inspiration. The authors thank Susanna Brusa for graphical support. The authors acknowledge support from the University of Milan through the APC initiative.
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VM and CG contributed to the study conception and design. VM, CG, CP, and AL wrote the original draft of the manuscript; CP, AL, and PG performed most laboratory work and analyses; GF and SR performed RNAseq experiments and analyzed data; SG and SP performed sfingolipid analysis and AP supervised and designed the lipid experiments; EDF, ET, AT, EAC, SR, and AC assisted in performing experiments; MM and AS contributed assessing and discussing the clinical relevance of results; SC provided cell lines and assisted in BOs generation; PF discussed genetic relevance of experiments; LC supervised/assisted experiments and provided cell lines; all authors edited and reviewed the manuscript. All authors read and approved the final manuscript.
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Parodi, C., Lettieri, A., Grazioli, P. et al. Lithium ameliorates neural differentiation restoring cell death balance in Cornelia de Lange syndrome 2D and 3D models. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03085-z
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DOI: https://doi.org/10.1038/s41420-026-03085-z
