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 WD, 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. Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions. Neuron. 2024 Sep 4;112(17):2886-2909.e16. Epub 2024 Jul 29 PubMed.
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Emory University
Rudolf Virchow, the founder of cellular pathology, would have been thrilled, and perhaps even awestruck, to have witnessed this sweeping investigation of the formation and molecular characteristics of α-synuclein cellular inclusions. The novel cell lines described by Lam and colleagues derive from induced pluripotent stem cells that are transdifferentiated into either astrocytes or a specific type of cortical neuron. Because such in vitro cellular models allow researchers to efficiently manipulate genetic, physiological, and environmental variables, and to follow the consequences longitudinally, they can yield insights into cellular pathology that are impossible to glean from postmortem histopathological studies in humans. The researchers acknowledge possible pitfalls of extrapolating from simple, and somewhat artificial, models to complex and variable organisms such as humans, but the shortcomings are far outweighed by the ability to rapidly test both mechanistic hypotheses and potential therapeutics. The most auspicious insights can then be applied with reasonable confidence to more advanced biological systems.
I encourage the reader to peruse this multifaceted and enjoyable report firsthand, but a finding that I found particularly intriguing was the divergent pathogenicity of lipid-rich versus fibril-rich α-synuclein inclusions, along with evidence that the different lesions can merge within the cells. The authors identify candidate molecules/pathways that might influence the toxicity of lipid-rich inclusions, but how a type of fibril-rich inclusion protects the cells is a salient unknown.
A related issue that the model can illuminate is whether the inclusions are distinct structures or different developmental stages of a single entity. The ability to analyze the fine structural and molecular components of the inclusions is especially useful, both to characterize their similarities and differences, and to reveal promising therapeutic targets.
Finally, the translational potential of the study is strengthened by the explicit comparison of the features observed in the cellular models to inclusions in the human brain. In light of the expanding technical capacity to generate cell types in vitro that reflect as closely as possible their counterparts in vivo, I have little doubt that these models will play an increasingly important role in mechanistic investigations of neurodegenerative diseases.
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