Journal Article

DKFZ-2025-02103

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids.

Zillich, L. (First author)DKFZ* ; Gasparotto, M. (First author)DKFZ* ; Rossetti, A. C. (First author)DKFZ* ; Fechtner, O. (First author)DKFZ* ; Maillard, C. ; Hoffrichter, A.DKFZ* ; Zillich, E. ; Jabali, A.DKFZ* ; Marsoner, F.DKFZ* ; Artioli, A.DKFZ* ; Wilkens, R.DKFZ* ; Schroeter, C. B. ; Hentschel, A. ; Witt, S. H. ; Melzer, N. ; Meuth, S. G. ; Ruck, T. ; Koch, P.DKFZ* ; Roos, A. ; Bahi-Buisson, N. ; Francis, F. ; Ladewig, J. (Last author)DKFZ*

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-64980-0

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.

Keyword(s): Organoids: metabolism (MeSH) ; Organoids: pathology (MeSH) ; Humans (MeSH) ; Prosencephalon: metabolism (MeSH) ; Prosencephalon: pathology (MeSH) ; Proteostasis: genetics (MeSH) ; Microtubule-Associated Proteins: genetics (MeSH) ; Microtubule-Associated Proteins: metabolism (MeSH) ; Lissencephaly: genetics (MeSH) ; Lissencephaly: metabolism (MeSH) ; Lissencephaly: pathology (MeSH) ; 1-Alkyl-2-acetylglycerophosphocholine Esterase: genetics (MeSH) ; 1-Alkyl-2-acetylglycerophosphocholine Esterase: metabolism (MeSH) ; Mutation (MeSH) ; Neurogenesis: genetics (MeSH) ; Mechanistic Target of Rapamycin Complex 1: metabolism (MeSH) ; Mechanistic Target of Rapamycin Complex 1: antagonists & inhibitors (MeSH) ; Severity of Illness Index (MeSH) ; Wnt Signaling Pathway (MeSH) ; Proteomics (MeSH) ; Neural Stem Cells: metabolism (MeSH) ; Microtubules: metabolism (MeSH) ; Female (MeSH) ; Microtubule-Associated Proteins ; PAFAH1B1 protein, human ; 1-Alkyl-2-acetylglycerophosphocholine Esterase ; Mechanistic Target of Rapamycin Complex 1

Note: #EA:A340#LA:A340#

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Contributing Institute(s):

1. A340 NWG Engeneering von Zellidentitäten und Krankheitsmodellen (A340)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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