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