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Al-Ramahi, I., Lu, B., Di Paola, S., Pang, K., de Haro, M., Peluso, I., Gallego-Flores, T., Malik, N.T., Erikson, K., Bleiberg, B.A., Avalos, M., Fan, G., Rivers, L.E., Laitman, A.M., Diaz-García, J.R., Hild, M., Palacino, J., Liu, Z., Medina, D.L., Botas, J. (2018). High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration.  Cell Syst. 7(1): 28--40.e4.
FlyBase ID
FBrf0239560
Publication Type
Research paper
Abstract

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 macroautophagy, 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.

PubMed ID
PubMed Central ID
PMC6082401 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Cell Syst.
    Title
    Cell systems
    ISBN/ISSN
    2405-4720 2405-4712
    Data From Reference