%0 Journal Article
%A Zillich, Lea
%A Gasparotto, Matteo
%A Rossetti, Andrea Carlo
%A Fechtner, Olivia
%A Maillard, Camille
%A Hoffrichter, Anne
%A Zillich, Eric
%A Jabali, Ammar
%A Marsoner, Fabio
%A Artioli, Annasara
%A Wilkens, Ruven
%A Schroeter, Christina B
%A Hentschel, Andreas
%A Witt, Stephanie H
%A Melzer, Nico
%A Meuth, Sven G
%A Ruck, Tobias
%A Koch, Philipp
%A Roos, Andreas
%A Bahi-Buisson, Nadia
%A Francis, Fiona
%A Ladewig, Julia
%T Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids.
%J Nature Communications
%V 16
%N 1
%@ 2041-1723
%C [London]
%I Springer Nature
%M DKFZ-2025-02103
%P 9091
%D 2025
%Z #EA:A340#LA:A340#
%X 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.
%K Organoids: metabolism
%K Organoids: pathology
%K Humans
%K Prosencephalon: metabolism
%K Prosencephalon: pathology
%K Proteostasis: genetics
%K Microtubule-Associated Proteins: genetics
%K Microtubule-Associated Proteins: metabolism
%K Lissencephaly: genetics
%K Lissencephaly: metabolism
%K Lissencephaly: pathology
%K 1-Alkyl-2-acetylglycerophosphocholine Esterase: genetics
%K 1-Alkyl-2-acetylglycerophosphocholine Esterase: metabolism
%K Mutation
%K Neurogenesis: genetics
%K Mechanistic Target of Rapamycin Complex 1: metabolism
%K Mechanistic Target of Rapamycin Complex 1: antagonists & inhibitors
%K Severity of Illness Index
%K Wnt Signaling Pathway
%K Proteomics
%K Neural Stem Cells: metabolism
%K Microtubules: metabolism
%K Female
%K Microtubule-Associated Proteins (NLM Chemicals)
%K PAFAH1B1 protein, human (NLM Chemicals)
%K 1-Alkyl-2-acetylglycerophosphocholine Esterase (NLM Chemicals)
%K Mechanistic Target of Rapamycin Complex 1 (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41083500
%R 10.1038/s41467-025-64980-0
%U https://inrepo02.dkfz.de/record/305359