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| Home > Publications database > Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids. > print |
| Home > Publications database > Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids. > print |
| 001 | 305359 | ||
| 005 | 20251019023220.0 | ||
| 024 | 7 | _ | |a 10.1038/s41467-025-64980-0 |2 doi |
| 024 | 7 | _ | |a pmid:41083500 |2 pmid |
| 024 | 7 | _ | |a altmetric:182560346 |2 altmetric |
| 037 | _ | _ | |a DKFZ-2025-02103 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 500 |
| 100 | 1 | _ | |a Zillich, Lea |0 0000-0001-7457-374X |b 0 |e First author |
| 245 | _ | _ | |a Capturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids. |
| 260 | _ | _ | |a [London] |c 2025 |b Springer Nature |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1760447291_18623 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 500 | _ | _ | |a #EA:A340#LA:A340# |
| 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. |
| 536 | _ | _ | |a 311 - Zellbiologie und Tumorbiologie (POF4-311) |0 G:(DE-HGF)POF4-311 |c POF4-311 |f POF IV |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de |
| 650 | _ | 7 | |a Microtubule-Associated Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a PAFAH1B1 protein, human |0 EC 3.1.1.47 |2 NLM Chemicals |
| 650 | _ | 7 | |a 1-Alkyl-2-acetylglycerophosphocholine Esterase |0 EC 3.1.1.47 |2 NLM Chemicals |
| 650 | _ | 7 | |a Mechanistic Target of Rapamycin Complex 1 |0 EC 2.7.11.1 |2 NLM Chemicals |
| 650 | _ | 2 | |a Organoids: metabolism |2 MeSH |
| 650 | _ | 2 | |a Organoids: pathology |2 MeSH |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Prosencephalon: metabolism |2 MeSH |
| 650 | _ | 2 | |a Prosencephalon: pathology |2 MeSH |
| 650 | _ | 2 | |a Proteostasis: genetics |2 MeSH |
| 650 | _ | 2 | |a Microtubule-Associated Proteins: genetics |2 MeSH |
| 650 | _ | 2 | |a Microtubule-Associated Proteins: metabolism |2 MeSH |
| 650 | _ | 2 | |a Lissencephaly: genetics |2 MeSH |
| 650 | _ | 2 | |a Lissencephaly: metabolism |2 MeSH |
| 650 | _ | 2 | |a Lissencephaly: pathology |2 MeSH |
| 650 | _ | 2 | |a 1-Alkyl-2-acetylglycerophosphocholine Esterase: genetics |2 MeSH |
| 650 | _ | 2 | |a 1-Alkyl-2-acetylglycerophosphocholine Esterase: metabolism |2 MeSH |
| 650 | _ | 2 | |a Mutation |2 MeSH |
| 650 | _ | 2 | |a Neurogenesis: genetics |2 MeSH |
| 650 | _ | 2 | |a Mechanistic Target of Rapamycin Complex 1: metabolism |2 MeSH |
| 650 | _ | 2 | |a Mechanistic Target of Rapamycin Complex 1: antagonists & inhibitors |2 MeSH |
| 650 | _ | 2 | |a Severity of Illness Index |2 MeSH |
| 650 | _ | 2 | |a Wnt Signaling Pathway |2 MeSH |
| 650 | _ | 2 | |a Proteomics |2 MeSH |
| 650 | _ | 2 | |a Neural Stem Cells: metabolism |2 MeSH |
| 650 | _ | 2 | |a Microtubules: metabolism |2 MeSH |
| 650 | _ | 2 | |a Female |2 MeSH |
| 700 | 1 | _ | |a Gasparotto, Matteo |0 P:(DE-He78)e527c65a82968365db461f1f682244a9 |b 1 |e First author |u dkfz |
| 700 | 1 | _ | |a Rossetti, Andrea Carlo |0 P:(DE-He78)6a89b714b460f280aa0754d314050a75 |b 2 |e First author |
| 700 | 1 | _ | |a Fechtner, Olivia |0 P:(DE-HGF)0 |b 3 |e First author |
| 700 | 1 | _ | |a Maillard, Camille |b 4 |
| 700 | 1 | _ | |a Hoffrichter, Anne |0 P:(DE-He78)8fef0750586db773a17bf744ffa6a243 |b 5 |u dkfz |
| 700 | 1 | _ | |a Zillich, Eric |0 0000-0003-3704-7243 |b 6 |
| 700 | 1 | _ | |a Jabali, Ammar |0 P:(DE-HGF)0 |b 7 |
| 700 | 1 | _ | |a Marsoner, Fabio |0 P:(DE-HGF)0 |b 8 |
| 700 | 1 | _ | |a Artioli, Annasara |0 P:(DE-He78)8c598f21282683b7400b73db6eb37f34 |b 9 |u dkfz |
| 700 | 1 | _ | |a Wilkens, Ruven |0 P:(DE-HGF)0 |b 10 |
| 700 | 1 | _ | |a Schroeter, Christina B |0 0000-0002-1391-7817 |b 11 |
| 700 | 1 | _ | |a Hentschel, Andreas |b 12 |
| 700 | 1 | _ | |a Witt, Stephanie H |0 0000-0002-1571-1468 |b 13 |
| 700 | 1 | _ | |a Melzer, Nico |0 0000-0002-2420-701X |b 14 |
| 700 | 1 | _ | |a Meuth, Sven G |0 0000-0003-2571-3501 |b 15 |
| 700 | 1 | _ | |a Ruck, Tobias |0 0000-0001-6332-8650 |b 16 |
| 700 | 1 | _ | |a Koch, Philipp |0 P:(DE-He78)7622d683a69f6d26d04f928d1b15d64b |b 17 |
| 700 | 1 | _ | |a Roos, Andreas |b 18 |
| 700 | 1 | _ | |a Bahi-Buisson, Nadia |b 19 |
| 700 | 1 | _ | |a Francis, Fiona |0 0000-0001-8542-7537 |b 20 |
| 700 | 1 | _ | |a Ladewig, Julia |0 P:(DE-He78)39b28715a3581ccbfe6d3d91dd98ce26 |b 21 |e Last author |
| 773 | _ | _ | |a 10.1038/s41467-025-64980-0 |g Vol. 16, no. 1, p. 9091 |0 PERI:(DE-600)2553671-0 |n 1 |p 9091 |t Nature Communications |v 16 |y 2025 |x 2041-1723 |
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