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Transcriptional profiling in microglia across physiological and pathological states identifies a transcriptional
Aysegul Guvenek1,2, Neelroop Parikshak1, Daria Zamolodchikov2
1Regeneron Genetics Center, Tarrytown, NY, USA.
Abstract:
Microglia are the resident immune cells of the central nervous system and are involved in brain development, homeostasis, and disease. New imaging and genomics technologies are revealing microglial complexity across developmental and functional states, brain regions, and diseases. We curated a set of publicly available gene expression datasets from human microglia spanning disease and health to identify sets of genes reflecting physiological and pathological microglial states. We also integrated multiple human microglial single-cell RNA-seq datasets in Alzheimer's disease (AD), multiple sclerosis (MS), and Parkinson's disease, and identified a distinct microglial transcriptional signature shared across diseases. Analysis of germ-line DNA identified genes with variants associated with AD and MS that are overrepresented in microglial gene sets, including the disease-associated transcriptional signature. This work points to genes that are dysregulated in disease states and provides a resource for the analysis of diseases in which microglia are implicated by genetic evidence.
Insights
Researchers identified a shared microglial gene signature across neurological diseases like Alzheimer's and Parkinson's. This discovery highlights key genes dysregulated in disease, offering a resource for future research.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are crucial immune cells in the central nervous system, vital for brain health and disease.
- Advanced imaging and genomics reveal increasing complexity in microglial states across development, function, and disease.
- Understanding microglial roles is key to developing treatments for neurological disorders.
Purpose of the Study:
- To identify gene sets reflecting physiological and pathological microglial states.
- To uncover a common microglial transcriptional signature across major neurological diseases.
- To investigate the genetic underpinnings of microglial involvement in diseases like Alzheimer's, Multiple Sclerosis, and Parkinson's.
Main Methods:
- Curated and analyzed publicly available human microglial gene expression datasets from health and disease states.
- Integrated multiple human microglial single-cell RNA-seq datasets from Alzheimer's, Multiple Sclerosis, and Parkinson's disease patients.
- Analyzed germ-line DNA to identify gene variants associated with neurological diseases and their overrepresentation in microglial gene sets.
Main Results:
- Identified distinct microglial transcriptional signatures, with a notable signature shared across Alzheimer's, Multiple Sclerosis, and Parkinson's disease.
- Found that genes with variants linked to Alzheimer's and Multiple Sclerosis are enriched within microglial gene sets, including the shared disease signature.
- Established a comprehensive resource of genes dysregulated in microglial disease states.
Conclusions:
- Microglia exhibit conserved transcriptional responses across different neurological diseases.
- Genetic factors influencing Alzheimer's and Multiple Sclerosis risk are linked to microglial gene expression patterns.
- This study provides valuable insights and a resource for understanding microglial roles in neurological diseases.
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