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Lithium ameliorates neural differentiation restoring cell death balance in Cornelia de Lange syndrome 2D and 3D models.

Overview

Authors: Chiara Parodi1, Antonella Lettieri1, Paolo Grazioli1, Elisabetta Di Fede1,2, Sara Grassi3, Esi Taci1,2, Andrea Toscani1,2, Simona Prioni3, Stefano Rebellato4, Elisa Adele Colombo1, Silvia Rasetti1,2, Alessandro Cutarelli5, Milena Mariani6, Stefania Corti7, Palma Finelli8, Alessandro Prinetti3, Grazia Fazio4,9, Angelo Selicorni6, Luciano Conti5, Cristina Gervasini1,2, Valentina Massa1,2
ORCID iDs: Chiara Parodi, Paolo Grazioli, Sara Grassi, Esi Taci, Silvia Rasetti, Alessandro Cutarelli, Grazia Fazio, Luciano Conti, Valentina Massa
  1. Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
  2. “Aldo Ravelli” Center for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy
  3. Department of Medical Biotechnology and Translational Medicine, University of Milano, Segrate, Milano, Italy
  4. Tettamanti Center, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
  5. Dipartimento di Biologia Cellulare, Computazionale e Integrata - CIBIO, Trento, Italy
  6. U.O. di Pediatria dell’ASST Lariana, Como, Italy
  7. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
  8. SS Medical Genetics Laboratory, SC Clinical Pathology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
  9. School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
Institutions: University of Milan (Italy); University of Trento (Italy); Azienda Socio Sanitaria Territoriale Lariana (Italy); Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Italy); University of Milano-Bicocca (Italy)
Journal: Cell death discovery, volume 12, issue 1, article 203
Dates: received 17 December 2025; accepted 12 March 2026; published online 28 March 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1038/s41420-026-03085-z · PMID 41904182 · PMCID PMC13150035 · OpenAlex W7142015151
Open access: gold, a free copy (OpenAlex)
Status: data only (how the code is found and verified)
Categories: human (organism), other condition (population)
Methods: Statistics
Keywords: Neurodevelopmental disorders, Translational research
Topic: Genomics and Chromatin Dynamics (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: Fondazione Cariplo (Cariplo Foundation) (GJC21149); Telethon (GJC21149)
Citations: not cited yet (Europe PMC); 38 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Data links

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 21 authors, 2 keywords, 2 funders, 38 references.

Cite

This paper

Parodi, C., Lettieri, A., Grazioli, P., Di Fede, E., Grassi, S., Taci, E., Toscani, A., Prioni, S., Rebellato, S., Colombo, E. A., Rasetti, S., Cutarelli, A., Mariani, M., Corti, S., Finelli, P., Prinetti, A., Fazio, G., Selicorni, A., Conti, L., . . . Massa, V. (2026). Lithium ameliorates neural differentiation restoring cell death balance in Cornelia de Lange syndrome 2D and 3D models. Cell death discovery, 12(1), 203. https://doi.org/10.1038/s41420-026-03085-z

BibTeX

@article{parodi2026lithium,
author = {Parodi, Chiara and Lettieri, Antonella and Grazioli, Paolo and Di Fede, Elisabetta and Grassi, Sara and Taci, Esi and Toscani, Andrea and Prioni, Simona and Rebellato, Stefano and Colombo, Elisa Adele and Rasetti, Silvia and Cutarelli, Alessandro and Mariani, Milena and Corti, Stefania and Finelli, Palma and Prinetti, Alessandro and Fazio, Grazia and Selicorni, Angelo and Conti, Luciano and Gervasini, Cristina and Massa, Valentina},
title = {{Lithium ameliorates neural differentiation restoring cell death balance in Cornelia de Lange syndrome 2D and 3D models}},
journal = {Cell death discovery},
year = {2026},
month = mar,
volume = {12},
number = {1},
pages = {203},
publisher = {Nature Publishing Group},
issn = {2058-7716},
doi = {10.1038/s41420-026-03085-z},
url = {https://doi.org/10.1038/s41420-026-03085-z},
pmid = {41904182},
pmcid = {PMC13150035}
}

RIS

TY - JOUR
AU - Parodi, Chiara
AU - Lettieri, Antonella
AU - Grazioli, Paolo
AU - Di Fede, Elisabetta
AU - Grassi, Sara
AU - Taci, Esi
AU - Toscani, Andrea
AU - Prioni, Simona
AU - Rebellato, Stefano
AU - Colombo, Elisa Adele
AU - Rasetti, Silvia
AU - Cutarelli, Alessandro
AU - Mariani, Milena
AU - Corti, Stefania
AU - Finelli, Palma
AU - Prinetti, Alessandro
AU - Fazio, Grazia
AU - Selicorni, Angelo
AU - Conti, Luciano
AU - Gervasini, Cristina
AU - Massa, Valentina
TI - Lithium ameliorates neural differentiation restoring cell death balance in Cornelia de Lange syndrome 2D and 3D models
T2 - Cell death discovery
J2 - Cell Death Discov
PY - 2026
DA - 2026/03/28
VL - 12
IS - 1
SP - 203
SN - 2058-7716
PB - Nature Publishing Group
DO - 10.1038/s41420-026-03085-z
UR - https://doi.org/10.1038/s41420-026-03085-z
LA - en
ER -

CSL-JSON

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