Verma, AmritaLam, IsabelNdayisaba, AlainLewis, Amanda J.Fu, YuHongSagredo, Giselle T.Kuzkina, AnastasiaZaccagnini, LudovicaCelikag, MeralSandoe, JacksonSanz, Ricardo L.Vahdatshoar, AazamMartin, Timothy D.Morshed, NaderIchihashi, ToruTripathi, AaratiRamalingam, NagendramOettgen-Suazo, CharlotteBartels, TheresaBoussouf, ManelSchäbinger, MaxHallacli, ErincJiang, XinTea, ChallanaWang, ZichenHakozaki, HiroyukiYu, XiaoHyles, KellyPark, ChansaemWang, XinyuanTheunissen, Thorold W.Wang, HanJaenisch, RudolfLindquist, SusanStevens, BethStefanova, NadiaWenning, Gregorvan de Berg, Wilma D.J.Luk, Kelvin C.Sanchez-Pernaute, R.Gómez-Esteban, J.C.Felsky, DanielKiyota, YasujiroSahni, NidhiYi, S. StephenChung, Chee YeungStahlberg, HenningFerrer, Isidro (Ferrer Abizanda)Schöneberg, JohannesElledge, Stephen J.Dettmer, UlfHalliday, Glenda M.Bartels, TimKhurana, Vikram2024-11-182024-11-182024-12-010896-6273https://hdl.handle.net/2445/216585The heterogeneity of protein-rich inclusions and its significance in neurodegeneration is poorly understood. Standard patient-derived iPSC models develop inclusions neither reproducibly nor in a reasonable time frame. Here, we developed screenable iPSC "inclusionopathy" models utilizing piggyBac or targeted transgenes to rapidly induce CNS cells that express aggregation-prone proteins at brain-like levels. Inclusions and their effects on cell survival were trackable at single-inclusion resolution. Exemplar cortical neuron α-synuclein inclusionopathy models were engineered through transgenic expression of α-synuclein mutant forms or exogenous seeding with fibrils. We identified multiple inclusion classes, including neuroprotective p62-positive inclusions versus dynamic and neurotoxic lipid-rich inclusions, both identified in patient brains. Fusion events between these inclusion subtypes altered neuronal survival. Proteome-scale α-synuclein genetic- and physical-interaction screens pinpointed candidate RNA-processing and actin-cytoskeleton-modulator proteins like RhoA whose sequestration into inclusions could enhance toxicity. These tractable CNS models should prove useful in functional genomic analysis and drug development for proteinopathies.41 p.application/pdfengcc by (c) Verma, Amrita et al., 2024https://creativecommons.org/licenses/by/4.0/CervellNeuronesDemènciaCèl·lules mareBrainNeuronsDementiaStem cellsinfo:eu-repo/semantics/article7518482024-11-18info:eu-repo/semantics/openAccess39079530