%0 Journal Article
%T Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions.
%A Lam I
%A Ndayisaba A
%A Lewis AJ
%A Fu Y
%A Sagredo GT
%A Kuzkina A
%A Zaccagnini L
%A Celikag M
%A Sandoe J
%A Sanz RL
%A Vahdatshoar A
%A Martin TD
%A Morshed N
%A Ichihashi T
%A Tripathi A
%A Ramalingam N
%A Oettgen-Suazo C
%A Bartels T
%A Boussouf M
%A Schäbinger M
%A Hallacli E
%A Jiang X
%A Verma A
%A Tea C
%A Wang Z
%A Hakozaki H
%A Yu X
%A Hyles K
%A Park C
%A Wang X
%A Theunissen TW
%A Wang H
%A Jaenisch R
%A Lindquist S
%A Stevens B
%A Stefanova N
%A Wenning G
%A van de Berg WDJ
%A Luk KC
%A Sanchez-Pernaute R
%A Gómez-Esteban JC
%A Felsky D
%A Kiyota Y
%A Sahni N
%A Yi SS
%A Chung CY
%A Stahlberg H
%A Ferrer I
%A Schöneberg J
%A Elledge SJ
%A Dettmer U
%A Halliday GM
%A Bartels T
%A Khurana V
%J Neuron
%V 112
%N 17
%D 2024 Sep 4
%M 39079530
%F 18.688
%R 10.1016/j.neuron.2024.06.002
%X 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.