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 represent...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
13 October 2025
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| In: |
Nature Communications
Year: 2025, Volume: 16, Pages: 1-16 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-025-64980-0 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-64980-0 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-64980-0 
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| Author Notes: | 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 & Julia Ladewig |
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| 520 | |a 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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