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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/216585
Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions
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The 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.
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VERMA, Amrita, LAM, Isabel, NDAYISABA, Alain, LEWIS, Amanda j., FU, Yuhong, SAGREDO, Giselle t., KUZKINA, Anastasia, ZACCAGNINI, Ludovica, CELIKAG, Meral, SANDOE, Jackson, SANZ, Ricardo l., VAHDATSHOAR, Aazam, MARTIN, Timothy d., MORSHED, Nader, ICHIHASHI, Toru, TRIPATHI, Aarati, RAMALINGAM, Nagendram, OETTGEN-SUAZO, Charlotte, BARTELS, Theresa, BOUSSOUF, Manel, SCHÄBINGER, Max, HALLACLI, Erinc, JIANG, Xin, TEA, Challana, WANG, Zichen, HAKOZAKI, Hiroyuki, YU, Xiao, HYLES, Kelly, PARK, Chansaem, WANG, Xinyuan, THEUNISSEN, Thorold w., WANG, Han, JAENISCH, Rudolf, LINDQUIST, Susan, STEVENS, Beth, STEFANOVA, Nadia, WENNING, Gregor, VAN DE BERG, Wilma d.j., LUK, Kelvin c., SANCHEZ-PERNAUTE, R., GÓMEZ-ESTEBAN, J.c., FELSKY, Daniel, KIYOTA, Yasujiro, SAHNI, Nidhi, YI, S. stephen, CHUNG, Chee yeung, STAHLBERG, Henning, FERRER, Isidro (ferrer abizanda), SCHÖNEBERG, Johannes, ELLEDGE, Stephen j., DETTMER, Ulf, HALLIDAY, Glenda m., BARTELS, Tim, KHURANA, Vikram. Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions. _Neuron_. 2024. Vol. 112, núm. 17, pàgs. 2886-2909. [consulta: 20 de gener de 2026]. ISSN: 0896-6273. [Disponible a: https://hdl.handle.net/2445/216585]