Lam, Isabel;
Ndayisaba, Alain;
Lewis, Amanda J;
Fu, YuHong;
Sagredo, Giselle T;
Kuzkina, Anastasia;
Zaccagnini, Ludovica;
... Khurana, Vikram; + view all
(2024)
Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions.
Neuron
10.1016/j.neuron.2024.06.002.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.neuron.2024.06.002 |
| Publisher version: | http://dx.doi.org/10.1016/j.neuron.2024.06.002 |
| Language: | English |
| Additional information: | © 2024 The Authors. Published by Elsevier Inc. under a Creative Commons license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | iPSC, neurodegeneration, inclusion, α-synuclein, Lewy body, neuron, glia, Parkinson’s disease, synucleinopathy, piggyBac, p62, ubiquitin, lipid, CRISPR screen, proximity labeling, dementia with Lewy bodies, RhoA, actin cytoskeleton, aggregation. Rab protein |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10195384 |
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