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000305359 1001_ $$00000-0001-7457-374X$$aZillich, Lea$$b0$$eFirst author
000305359 245__ $$aCapturing disease severity in LIS1-lissencephaly reveals proteostasis dysregulation in patient-derived forebrain organoids.
000305359 260__ $$a[London]$$bSpringer Nature$$c2025
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000305359 520__ $$aLIS1-lissencephaly is a neurodevelopmental disorder marked by reduced cortical folding and severe neurological impairment. Although all cases result from heterozygous mutations in the LIS1 gene, patients present a broad spectrum of severity. Here, we use patient-derived forebrain organoids representing mild, moderate, and severe LIS1-lissencephaly to uncover mechanisms underlying this variability. We show that LIS1 protein levels vary across patient lines and partly correlate with clinical severity, indicating mutation-specific effects on protein function. Integrated morphological, transcriptomic, and proteomic analyses reveal progressive changes in neural progenitor homeostasis and neurogenesis that scale with severity. Mechanistically, microtubule destabilization disrupts cell-cell junctions and impairs WNT signaling, and defects in protein homeostasis, causing stress from misfolded proteins, emerge as key severity-linked pathways. Pharmacological inhibition of mTORC1 partially rescues these defects. Our findings demonstrate that patient-derived organoids can model disease severity, enabling mechanistic dissection and guiding targeted strategies in neurodevelopmental disorders.
000305359 536__ $$0G:(DE-HGF)POF4-311$$a311 - Zellbiologie und Tumorbiologie (POF4-311)$$cPOF4-311$$fPOF IV$$x0
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000305359 650_7 $$2NLM Chemicals$$aMicrotubule-Associated Proteins
000305359 650_7 $$0EC 3.1.1.47$$2NLM Chemicals$$aPAFAH1B1 protein, human
000305359 650_7 $$0EC 3.1.1.47$$2NLM Chemicals$$a1-Alkyl-2-acetylglycerophosphocholine Esterase
000305359 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aMechanistic Target of Rapamycin Complex 1
000305359 650_2 $$2MeSH$$aOrganoids: metabolism
000305359 650_2 $$2MeSH$$aOrganoids: pathology
000305359 650_2 $$2MeSH$$aHumans
000305359 650_2 $$2MeSH$$aProsencephalon: metabolism
000305359 650_2 $$2MeSH$$aProsencephalon: pathology
000305359 650_2 $$2MeSH$$aProteostasis: genetics
000305359 650_2 $$2MeSH$$aMicrotubule-Associated Proteins: genetics
000305359 650_2 $$2MeSH$$aMicrotubule-Associated Proteins: metabolism
000305359 650_2 $$2MeSH$$aLissencephaly: genetics
000305359 650_2 $$2MeSH$$aLissencephaly: metabolism
000305359 650_2 $$2MeSH$$aLissencephaly: pathology
000305359 650_2 $$2MeSH$$a1-Alkyl-2-acetylglycerophosphocholine Esterase: genetics
000305359 650_2 $$2MeSH$$a1-Alkyl-2-acetylglycerophosphocholine Esterase: metabolism
000305359 650_2 $$2MeSH$$aMutation
000305359 650_2 $$2MeSH$$aNeurogenesis: genetics
000305359 650_2 $$2MeSH$$aMechanistic Target of Rapamycin Complex 1: metabolism
000305359 650_2 $$2MeSH$$aMechanistic Target of Rapamycin Complex 1: antagonists & inhibitors
000305359 650_2 $$2MeSH$$aSeverity of Illness Index
000305359 650_2 $$2MeSH$$aWnt Signaling Pathway
000305359 650_2 $$2MeSH$$aProteomics
000305359 650_2 $$2MeSH$$aNeural Stem Cells: metabolism
000305359 650_2 $$2MeSH$$aMicrotubules: metabolism
000305359 650_2 $$2MeSH$$aFemale
000305359 7001_ $$0P:(DE-He78)e527c65a82968365db461f1f682244a9$$aGasparotto, Matteo$$b1$$eFirst author$$udkfz
000305359 7001_ $$0P:(DE-He78)6a89b714b460f280aa0754d314050a75$$aRossetti, Andrea Carlo$$b2$$eFirst author
000305359 7001_ $$0P:(DE-HGF)0$$aFechtner, Olivia$$b3$$eFirst author
000305359 7001_ $$aMaillard, Camille$$b4
000305359 7001_ $$0P:(DE-He78)8fef0750586db773a17bf744ffa6a243$$aHoffrichter, Anne$$b5$$udkfz
000305359 7001_ $$00000-0003-3704-7243$$aZillich, Eric$$b6
000305359 7001_ $$0P:(DE-HGF)0$$aJabali, Ammar$$b7
000305359 7001_ $$0P:(DE-HGF)0$$aMarsoner, Fabio$$b8
000305359 7001_ $$0P:(DE-He78)8c598f21282683b7400b73db6eb37f34$$aArtioli, Annasara$$b9$$udkfz
000305359 7001_ $$0P:(DE-HGF)0$$aWilkens, Ruven$$b10
000305359 7001_ $$00000-0002-1391-7817$$aSchroeter, Christina B$$b11
000305359 7001_ $$aHentschel, Andreas$$b12
000305359 7001_ $$00000-0002-1571-1468$$aWitt, Stephanie H$$b13
000305359 7001_ $$00000-0002-2420-701X$$aMelzer, Nico$$b14
000305359 7001_ $$00000-0003-2571-3501$$aMeuth, Sven G$$b15
000305359 7001_ $$00000-0001-6332-8650$$aRuck, Tobias$$b16
000305359 7001_ $$0P:(DE-He78)7622d683a69f6d26d04f928d1b15d64b$$aKoch, Philipp$$b17
000305359 7001_ $$aRoos, Andreas$$b18
000305359 7001_ $$aBahi-Buisson, Nadia$$b19
000305359 7001_ $$00000-0001-8542-7537$$aFrancis, Fiona$$b20
000305359 7001_ $$0P:(DE-He78)39b28715a3581ccbfe6d3d91dd98ce26$$aLadewig, Julia$$b21$$eLast author
000305359 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-025-64980-0$$gVol. 16, no. 1, p. 9091$$n1$$p9091$$tNature Communications$$v16$$x2041-1723$$y2025
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