Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids

LIS1-lissencephaly is a neurodevelopmental disorder marked by reduced cortical folding and severe neurological impairment. Although all cases result from heterozygous mutations in the LIS1 gene, patients present a broad spectrum of severity. Here, we use patient-derived forebrain organoids representing mild, moderate, and severe LIS1-lissencephaly to uncover mechanisms underlying this variability. We show that LIS1 protein levels vary across patient lines and partly correlate with clinical severity, indicating mutation-specific effects on protein function. Integrated morphological, transcriptomic, and proteomic analyses reveal progressive changes in neural progenitor homeostasis and neurogenesis that scale with severity. Mechanistically, microtubule destabilization disrupts cell-cell junctions and impairs WNT signaling, and defects in protein homeostasis, causing stress from misfolded proteins, emerge as key severity-linked pathways. Pharmacological inhibition of mTORC1 partially rescues these defects. Our findings demonstrate that patient-derived organoids can model disease severity, enabling mechanistic dissection and guiding targeted strategies in neurodevelopmental disorders.

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Publication Details

Journal
Nature Communications
Published
2025-10-13
DOI
https://doi.org/10.1038/s41467-025-64980-0
Citations
2
Primary Topic
Hippo pathway signaling and YAP/TAZ
Type
article
Field-Weighted Citation Impact
2.30

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article

Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids

Eric Zillich, Annasara Artioli, Christina B. Schroeter, Nadia Bahi‐Buisson et al.
2 citations
Nature Communications
Hippo pathway signaling and YAP/TAZ
2.30
article

Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids

Eric Zillich, Annasara Artioli, Christina B. Schroeter, Nadia Bahi‐Buisson, Sven Guenther Meuth, Matteo Gasparotto, Andreas Hentschel, A.C. Rossetti, Tobias Ruck, Ammar Jabali, Stephanie H. Witt, Andreas Roos, Ruven Wilkens, Nico Melzer, Philipp Koch, Camille Maillard, Anne Hoffrichter, Julia Ladewig, Lea Zillich, Fiona Francis, Fabio Marsoner, Olivia Fechtner
article en
2 citations

Abstract

LIS1-lissencephaly is a neurodevelopmental disorder marked by reduced cortical folding and severe neurological impairment. Although all cases result from heterozygous mutations in the LIS1 gene, patients present a broad spectrum of severity. Here, we use patient-derived forebrain organoids representing mild, moderate, and severe LIS1-lissencephaly to uncover mechanisms underlying this variability. We show that LIS1 protein levels vary across patient lines and partly correlate with clinical severity, indicating mutation-specific effects on protein function. Integrated morphological, transcriptomic, and proteomic analyses reveal progressive changes in neural progenitor homeostasis and neurogenesis that scale with severity. Mechanistically, microtubule destabilization disrupts cell-cell junctions and impairs WNT signaling, and defects in protein homeostasis, causing stress from misfolded proteins, emerge as key severity-linked pathways. Pharmacological inhibition of mTORC1 partially rescues these defects. Our findings demonstrate that patient-derived organoids can model disease severity, enabling mechanistic dissection and guiding targeted strategies in neurodevelopmental disorders.

Nature CommunicationsVol. 16(1)
Technische Hochschule Mannheim (DE), Centre National de la Recherche Scientifique (FR), University of Bonn (DE), Inserm (FR), German Cancer Research Center (DE), Université Paris Cité (FR), Heidelberg University (DE), Children's Hospital of Eastern Ontario (CA), University Hospital Bonn (DE), University Hospital Heidelberg (DE), Sorbonne Université (FR), Düsseldorf University Hospital (DE), Central Institute of Mental Health (DE), Institut du Fer à Moulin (FR), BG University Hospital Bergmannsheil Bochum (DE), Institut des Maladies Génétiques Imagine (FR), Heinrich Heine University Düsseldorf (DE), University of Duisburg-Essen (DE)
Deutsches Krebsforschungszentrum, Associazione Italiana Rett, Bundesministerium für Bildung und Forschung, Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, Hector Stiftung, Hector Stiftung II
Openalex Percentile: Top 11%
Hippo pathway signaling and YAP/TAZ
2.30
DOIOpen Access PDFOpenAlex
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