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Status |
Public on May 31, 2017 |
Title |
Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Herewe optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (>85%) functional populations of spinal cord MNs and ACs. We identifysignificantlyincreased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionallyidentify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay thatcould guide future therapeutic strategies in ALS.
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Overall design |
Bulk RNA-seq at different timepoints throughout a 35-day differentiation protocol that converted iPSC cells to highly enriched motor neurons.
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Contributor(s) |
Hall C, Yao Z, Choi M, Tyzack G, Serio A, Luisier R, Harley J, Preza E, Arber C, Crisp SJ, Watson PM, Kullmann DM, Abramov A, Wray S, Burley R, Loh SH, Martins ML, Stevens MM, Luscombe N, Sibley C, Lakatos A, Ule J, Gandhi S, Patani R |
Citation(s) |
28564594, 29789581 |
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Submission date |
Apr 27, 2017 |
Last update date |
Jul 25, 2021 |
Contact name |
Raphaelle Luisier |
E-mail(s) |
raphaelle.luisier@gmail.com
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Phone |
0041762432198
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Organization name |
Idiap Research Institute
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Lab |
Genomics and Health Informatics
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Street address |
Rue Marconi 19, PO Box 592
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City |
Martigny |
State/province |
Valais |
ZIP/Postal code |
1920 |
Country |
Switzerland |
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Platforms (1) |
GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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Samples (20)
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This SubSeries is part of SuperSeries: |
GSE98290 |
Post-transcriptional remodelling is temporally deregulated during motor neurogenesis in human ALS models |
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Relations |
BioProject |
PRJNA384597 |
SRA |
SRP105349 |
Supplementary file |
Size |
Download |
File type/resource |
GSE98288_RAW.tar |
40.4 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
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