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

Lea Zillich, Matteo Gasparotto, Andrea Carlo Rossetti, Olivia Fechtner, Camille Maillard, Anne Hoffrichter, Eric Zillich, Ammar Jabali, Fabio Marsoner, Annasara Artioli, Ruven Wilkens, Christina B. Schroeter, Andreas Hentschel, Stephanie H. Witt, Nico Melzer, Sven G. Meuth, Tobias Ruck, Philipp Koch, Andreas Roos, Nadia Bahi-Buisson, Fiona Francis and Julia Ladewig ()
Additional contact information
Lea Zillich: Heidelberg University
Matteo Gasparotto: Heidelberg University
Andrea Carlo Rossetti: Heidelberg University
Olivia Fechtner: Heidelberg University
Camille Maillard: Imagine Institute
Anne Hoffrichter: Heidelberg University
Eric Zillich: Heidelberg University
Ammar Jabali: Heidelberg University
Fabio Marsoner: Heidelberg University
Annasara Artioli: Heidelberg University
Ruven Wilkens: Heidelberg University
Christina B. Schroeter: Heinrich Heine University Düsseldorf
Andreas Hentschel: BG University Hospital Bergmannsheil
Stephanie H. Witt: Heidelberg University
Nico Melzer: Heinrich Heine University Düsseldorf
Sven G. Meuth: Heinrich Heine University Düsseldorf
Tobias Ruck: BG University Hospital Bergmannsheil
Philipp Koch: Heidelberg University
Andreas Roos: Heinrich Heine University Düsseldorf
Nadia Bahi-Buisson: Imagine Institute
Fiona Francis: CNRS UMR 8265
Julia Ladewig: Heidelberg University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64980-0

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