Projects per year
Abstract
The molecular basis of how chromosome 16p13.11 microduplication leads to major psychiatric disorders is unknown. Here we have undertaken brain imaging of patients carrying microduplications in chromosome 16p13.11 and unaffected family controls, in parallel with iPS cell-derived cerebral organoid studies of the same patients. Patient MRI revealed reduced cortical volume, and corresponding iPSC studies showed neural precursor cell (NPC) proliferation abnormalities and reduced organoid size, with the NPCs therein displaying altered planes of cell division. Transcriptomic analyses of NPCs uncovered a deficit in the NFκB p65 pathway, confirmed by proteomics. Moreover, both pharmacological and genetic correction of this deficit rescued the proliferation abnormality. Thus, chromosome 16p13.11 microduplication disturbs the normal programme of NPC proliferation to reduce cortical thickness due to a correctable deficit in the NFκB signalling pathway. This is the first study demonstrating a biologically relevant, potentially ameliorable, signalling pathway underlying chromosome 16p13.11 microduplication syndrome in patient-derived neuronal precursor cells.
Original language | English |
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Pages (from-to) | 294-311 |
Number of pages | 18 |
Journal | Molecular Psychiatry |
Volume | 24 |
Issue number | 2 |
Early online date | 6 Nov 2018 |
DOIs | |
Publication status | Published - 28 Feb 2019 |
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Dive into the research topics of 'Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFκB signaling: An integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging'. Together they form a unique fingerprint.Projects
- 3 Finished
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Using Human Induced Pluripotent Stem Cells (iPSC) and iPAC-Derived Neurons to Explore Cellular Phenotypes Associated with Schizoprenia
Johnstone, M.
1/07/13 → 31/12/17
Project: Research
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Modelling psychosis using DISC1 human induced pluripotent stem cells
1/06/12 → 31/05/15
Project: Research
Profiles
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Neil Carragher
- Deanery of Molecular, Genetic and Population Health Sciences - Personal Chair of Drug Discovery
- Edinburgh Cancer Research Centre
Person: Academic: Research Active
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Siddharthan Chandran
- Deanery of Clinical Sciences - MacDonald Chair of Neurology
- Centre for Clinical Brain Sciences
- Euan MacDonald Centre for Motor Neuron Disease Research
- Centre for Regenerative Medicine
- Anne Rowling Regenerative Neurology Clinic
- Edinburgh Neuroscience
- Edinburgh Imaging
Person: Academic: Research Active