ArticleCell systems2018
High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration.
Article in Cell systems, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 45 citations in OpenAlex.
- Brain organoid models of Huntington's disease shift the focus towards neurodevelopment.Disease models & mechanisms · 2025Article
- Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures.Molecular systems biology · 2025Article
- Computational and functional prioritization identifies genes that rescue behavior and reduce tau protein in fly and human cell models of Alzheimer disease.American journal of human genetics · 2025Article
- Dendrite injury triggers neuroprotection in Drosophila models of neurodegenerative disease.Scientific reports · 2024Article
- Motor skill learning modulates striatal extracellular vesicles' content in a mouse model of Huntington's disease.Cell communication and signaling : CCS · 2024Article
- An altered extracellular matrix-integrin interface contributes to Huntington's disease-associated CNS dysfunction in glial and vascular cells.Human molecular genetics · 2023Article
- Integration of transcriptome-wide association study with neuronal dysfunction assays provides functional genomics evidence for Parkinson's disease genes.Human molecular genetics · 2023Article
- Single-nuclei transcriptome analysis of Huntington disease iPSC and mouse astrocytes implicates maturation and functional deficits.iScience · 2023Article
- Revisiting the outcome of adult wild-typeBrain communications · 2023Article
- Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders.Nature reviews. Neuroscience · 2023Review
- Emerging degrader technologies engaging lysosomal pathways.Chemical Society reviews · 2022Review
- Identification of risk genes for Alzheimer's disease by gene embedding.Cell genomics · 2022Article
- Modifier pathways in polyglutamine (PolyQ) diseases: from genetic screens to drug targets.Cellular and molecular life sciences : CMLS · 2022Review
- Dynamics of huntingtin protein interactions in the striatum identifies candidate modifiers of Huntington disease.Cell systems · 2022Article
- Gut Bacteria Regulate the Pathogenesis of Huntington's Disease inFrontiers in neuroscience · 2022Article
- Article
- Downregulation of glial genes involved in synaptic function mitigates Huntington's disease pathogenesis.eLife · 2021Article
- Increasing brain palmitoylation rescues behavior and neuropathology in Huntington disease mice.Science advances · 2021Article
- Article
- Integrated analysis of the aging brain transcriptome and proteome in tauopathy.Molecular neurodegeneration · 2020Article
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Authors and funding
20 authors at 5 institutions in 3 countries.
Funding
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.
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