TY  - JOUR
AU  - Zillich, Lea
AU  - Gasparotto, Matteo
AU  - Rossetti, Andrea Carlo
AU  - Fechtner, Olivia
AU  - Maillard, Camille
AU  - Hoffrichter, Anne
AU  - Zillich, Eric
AU  - Jabali, Ammar
AU  - Marsoner, Fabio
AU  - Artioli, Annasara
AU  - Wilkens, Ruven
AU  - Schroeter, Christina B
AU  - Hentschel, Andreas
AU  - Witt, Stephanie H
AU  - Melzer, Nico
AU  - Meuth, Sven G
AU  - Ruck, Tobias
AU  - Koch, Philipp
AU  - Roos, Andreas
AU  - Bahi-Buisson, Nadia
AU  - Francis, Fiona
AU  - Ladewig, Julia
TI  - Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-02103
SP  - 9091
PY  - 2025
N1  - #EA:A340#LA:A340#
AB  - 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.
KW  - Organoids: metabolism
KW  - Organoids: pathology
KW  - Humans
KW  - Prosencephalon: metabolism
KW  - Prosencephalon: pathology
KW  - Proteostasis: genetics
KW  - Microtubule-Associated Proteins: genetics
KW  - Microtubule-Associated Proteins: metabolism
KW  - Lissencephaly: genetics
KW  - Lissencephaly: metabolism
KW  - Lissencephaly: pathology
KW  - 1-Alkyl-2-acetylglycerophosphocholine Esterase: genetics
KW  - 1-Alkyl-2-acetylglycerophosphocholine Esterase: metabolism
KW  - Mutation
KW  - Neurogenesis: genetics
KW  - Mechanistic Target of Rapamycin Complex 1: metabolism
KW  - Mechanistic Target of Rapamycin Complex 1: antagonists & inhibitors
KW  - Severity of Illness Index
KW  - Wnt Signaling Pathway
KW  - Proteomics
KW  - Neural Stem Cells: metabolism
KW  - Microtubules: metabolism
KW  - Female
KW  - Microtubule-Associated Proteins (NLM Chemicals)
KW  - PAFAH1B1 protein, human (NLM Chemicals)
KW  - 1-Alkyl-2-acetylglycerophosphocholine Esterase (NLM Chemicals)
KW  - Mechanistic Target of Rapamycin Complex 1 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41083500
DO  - DOI:10.1038/s41467-025-64980-0
UR  - https://inrepo02.dkfz.de/record/305359
ER  -