Journal
CELL SYSTEMS
Volume 7, Issue 1, Pages 28-+Publisher
CELL PRESS
DOI: 10.1016/j.cels.2018.05.010
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Funding
- CHDI [A-6901]
- Robert A. and Renee E. Belfer Family Foundation
- NIH [NS42179, NRSA-NS043124, R21NS096395]
- Hereditary Disease Foundation
- Darrell K Royal Research Fund for Alzheimer's Disease
- Chinese Ministry of Science and Technology [2014AA02502]
- National Natural Science Foundation of China [31371421, 31422024]
- IDDRC from the Eunice Kennedy Shriver National Institute of Child Health AMP
- Human Development [1U54 HD083092]
- [NSF-DMS1263932]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [U54HD083092] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008307] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R21NS096395, T32NS043124, R01NS042179, R56NS042179] Funding Source: NIH RePORTER
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Discriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. This is particularly true for neurodegenerative diseases, which affect the expression of thousands of genes in different brain regions at different disease stages. Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice and then replicated and/or antagonized each alteration in a Drosophila HD model. High throughput behavioral testing in this model and controls revealed that transcriptional changes in synaptic biology and calcium signaling are compensatory, whereas alterations involving the actin cytoskeleton and inflammation drive disease. Knockdown of disease-driving genes in HD patient-derived cells lowered mutant Huntingtin levels and activated mac-roautophagy, suggesting a mechanism for mitigating pathogenesis. Our multilayered approach can thus untangle the wealth of information generated by transcriptomics and identify early therapeutic intervention points.
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